••• Office de Ia Proprit~te
`
`lntellectuelle
`du Canada
`Un organlsme
`d'lndustrie Canada
`
`Canadian
`Intellectual Property
`Office
`An agency of
`Industry Canada
`
`(22) Date de dep~t/Filing Date: 1994/05/25
`(41) Mise a Ia disp. pub./Open to Public Insp.: 1994/11/28
`(45) Date de delivrance/lssue Date: 2012/01/10
`(30) Priorites/Priorities: 1993/05/27 (GB931 097 4.2);
`1993/10/05 (GB9320463.4)
`
`CA 2124259 C 2012/01/10
`(11)(21) 2 124 259
`(12) BREVET CANADIEN
`CANADIAN PATENT
`(13) c
`
`(51) Cl.lnt/lntCI. B01J 13100(2006.01),
`A61K 9/107(2006.01}, A61K 9/48(2006.01},
`A61K 47110(2006.01}, A61K 47/44(2006.01}
`(72) lnventeurs/lnventors:
`FRICKER, GERD, DE;
`HAEBERLIN, BARBARA, CH;
`MEINZER, ARMIN, DE;
`VONDERSCHER, JACKY, FR
`(73) Proprietaire/Owner:
`NOV ARTIS AG, CH
`(74) Agent KIRBY EADES GALE BAKER
`
`(54) Titre : FORMES GALENIQUES
`(54) Title: GALENICAL FORMULATIONS•
`
`(57) Abrege/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 efficiency.
`
`c anaOa
`
`http://opic.gc.ca. Ottawa-Hull KIA OC9. http://cipo.gc.ca
`OPIC • CIPO 191
`
`0 PIC
`
`CI PO
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 001
`
`

`
`·
`
`c.,,~ -xtzs
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`
`2124259
`
`GALENICAL FORMULATIONS
`
`100·8039
`
`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
`
`5
`
`preconcentrates, emulsion or emulsion-preconcentrate.
`
`The macrolide may contain e.g. 1 , 2 or 3 ring oxygen or nitrogen or other atoms
`
`besides carbon atoms. It may have side chains, e.g. in the form of fused rings, or
`substituents,e.g. oxy groups. It may contain double bonds.
`
`It may contain e.g. from 15 to 35 ring atoms e.g. of carbon.
`
`1 0
`
`Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscoplcus. It
`has been found to be pharmaceutically 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:
`
`0
`
`'''1oH
`\
`
`(40)
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 002
`
`

`
`2121259
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`-2-
`
`Case 1 00-8039
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`(Kesseler, H., et al., Helv. Chim. Acta (1993) 12: 117; US Patent No.3 929 992}.
`Large numbers of derivatives of rapamycin have been synthesized, including for
`example those disclosed in US patents 5221670 and 5221740, certain acyl and
`amlnoacyl-rapamycins (see for example US patent 4316885, US patent 4650803,
`and US patent 5151413), 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 patent 5138051 }, alkoxyester derivatives
`(see for example US patent 5233036), and certain pyrazole derivatives (US patent
`5164399).
`Rapamycln and Its structurally similar analogs and derivatives are termed
`collectively as "compounds of the rapamycin class" in this specification.
`
`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 ~ariable bioavailabillty and their high toxicity. Little
`is known concerning the causes of these properties and the site of absorption. Thus
`low bloavallabillty may be thought to due to due to extensive metabolism of the
`macrolide ring and not solvable by a galenical formluatlon.
`Therefore there Is a need for an acceptable pharmaceutical composition that
`contains compounds of the rapamycin class.
`
`5
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`10
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`15
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`20
`
`FK506 Is a macrolide immunosuppressant that is produced by Streptomyces
`tsykubaeosjs No 9993. The structure of FK506 Is given in the appendix to the
`Merck Index, as Item AS. Also a large number of related compounds which retrain
`--------th-a·-basicsTructure-anaTmmunoraglcarpropertlesoTFIGOl:rare-arso known~fllese-----·--
`
`25
`
`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 91119495, EP 484936, EP 532088, EP 532089, WO 93/5059
`and the like. Little Is known concerning the biopharmaceutlcal properties of such
`compounds. These compounds are termed collectively "FK506 compounds" In this
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 003
`
`

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`r
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`· z
`
`rt mm~
`
`wn-u ere
`
`runs·· -ru·rr-·'m
`
`CA 02124259 2007-01-31
`
`-3-
`
`(
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`specification.
`
`It has now been surprisingly found that stable composition~ containing macrolides
`that offer high absorption efficiency, can be obtained by formulating the macrolide
`with certain carrier media.
`
`5
`
`Accordingly, this invention provides a pharmaceutical composition comprising a
`macrolide and a carrier medium comprising a hydrophilic phase, a llpophiHc phase
`and a surfactant.
`
`In another aspect the invention provides a pharmaceutical composition which
`comprises an orally administrable active agent which is other than a cyclosporin
`and a mtcroemulslon preconcentrate carrier medium therefor which comprises
`
`1 0
`
`i) a reaction product of castor oil and ethylene oxide,
`
`II) a transesteriflcation product of a vegetable oil and gly~rol comprising
`predominantly linoleic acid or oleic acid mono-, di- and trl-glycerides, or a
`polyoxyalkylated vegetable oil,
`
`15
`
`Iii} 1,2 propylene glycol and
`
`iv) ethanol.
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 004
`
`

`
`CA 02124259 2010-09-14
`
`-3a-
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`In one particular embodiment there is provided a pharmaceutical composition in the
`
`form of a microemulsion preconcentrate comprising rapamycin or
`
`40-0-(2-hydroxy)ethyl rapamycin as an active ingredient in a carrier medium which
`
`comprises: i) a hydrophilic phase; ii) a lipophilic phase selected from the group
`
`5
`
`consisting of medium chain fatty acid triglycerides, mixed mono-, di-, and
`
`tri-glycerides, and transesterified ethoxylated vegetable oils; iii) a surfactant selected
`
`from the group consisting of the reaction product of a natural or hydrogenated castor
`
`oil and ethylene oxide; polyethylene-sorbitan fatty acid esters, polyoxyethylene fatty
`
`acid esters, polyoxyethylene-polyoxypropylene co-polymers and block co-polymers,
`
`10
`
`dioctylsulfosuccinate or di(-2-ethylhexyl)-succinate, phospholipids, and propylene
`
`glycol mono- and di-fatty acid esters; the relative proportion of the active ingredient
`
`and components i), ii) and iii) being such that on dilution with water, a microemulsion
`having an average particle size of <1,500 A is spontaneously formed.
`
`15
`
`In another particular embo<;liment there is provided a pharmaceutical composition
`
`comprising a compound from the FK506 class and a carrier medium comprising a
`
`hydrophilic phase, a lipophilic phase and a surfactant.
`
`In a further particular embodiment there is provided a pharmaceutical composition
`
`20
`
`comprising a compound from the rapamycin class and a carrier medium comprising
`
`a hydrophilic phase, a lipophilic phase and a surfactant in the form of an emulsion
`
`preconcentrate.
`
`The pharmaceutical composition is stable and results in surprisingly high and
`
`25
`
`consistent absorption efficiency when administered orally. Therefore the macrolide
`
`may be administered 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
`
`._ph.arma.c_e_utic;:~L com(;)_o~itions have very surprising properties which offer great
`~-,-·- ------ -------""~----~----' --·-- -----------'~---- -------- -------- '"----------·-- -- -------- -------------- -
`
`advantages.
`
`30
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 005
`
`

`
`..
`
`(
`
`5
`
`1 0
`
`15
`
`20
`
`25
`
`OA 02124259 2007-01-31
`
`-4-
`
`Preferably the composition is in the form of a "microemulsion preconcentrate" or
`"emulsion preconcentrate", in particular of the type providing olw (oil-in-water)
`microemulsions or emulsions. However the composition may be In the form of a
`microemulslon or an emulsion which additionally contains an aqueous phase;
`preferably water.
`
`A "mlcroemulslon preconcentrate" is defined In this specification 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 "mlcroemulsion" 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 microemulslon Is thermodynamically stable and
`contains dispersed particles of a size less than about 2000 A. Generally
`mlcroemulslons comprise droplets or particles having a diameter of less than about
`1500 A; typically from 30 to 1000 A. Further characteristic can be found In British
`patent application 2 222 770 A.
`
`An "emulsion preconcentrate" is defined In this specification 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
`___ jlre!f~r tha~~~_!~P~~._ m~~-li_~':J~I}' Q~~te~_!h(l~~~-~~~ _l'l_l!l·_Oft_~~--- --~ _
`bimodal size range distributions are obtained. The emulsion preconcentrates 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 themselves pharmaceutically acceptable and, when
`a particular form of administration is foreseen, are suitable or acceptable for that
`form of administration.
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 006
`
`

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`212 4 2 ~; 9
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`-5-
`
`Case 1 00-8039
`
`The lipophilic phase may comprise 10 to 85 o/o 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 o/o by weight.
`
`5
`
`The surfactant may comprise 5 to 80% by weight of the carrier medium; preferably
`10 to 70 o/o by weight, more preferably 20 to 60 o/o by weight and even more
`preferably about 40 % by weight.
`
`The hydrophilic phase may comprise 1 0 to 50 o/o 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.
`
`1 0
`
`The macrolide is preferably present in an amount of 1 to 15 % by weight of the
`composition; more preferably about 2 to 10 %.
`
`15
`
`The macrolide may be rapamycin or an 0-substituted derivative in which the
`hydroxy in position 40 of the formula Illustrated above is replaced by -OR1 in which
`A1 is hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl and amlnoalkyl; for example 40-
`0-(2-hydroxy)ethyl-rapamycin, 40-0-(3-hydroxy)propyl-rapamycin, 40-0-[2-(2-
`hydroxy)ethoxy]ethyl-rapamycln and 40-0-(2-acetaminoethyl)-rapamycin. These 0-
`substituted derivatives may be produced by reacting Rapamycin (or dihydro or
`deoxor~pamycin) with an organic radical attached to a leaving group (for example
`RX where R is the organic radical which is desired as the 0-substituent, such as an
`alkyl, allyl, or benzyl moiety, and X is a leaving group such as CCI3C{NH)O or
`20
`- --- -----cF3so;ronae-rsultaole reaction condftlons-:-Tnecoiioltions-mayoe-acldlc or- ---- -- ----
`neutral conditions, for example in the presence of an acid like
`trlfluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their
`respective pyridlnium or substituted pyridinlum salts when X is CCI3C(NH)O or In
`the presence of a base like pyridine, a substituted pyridine, dilsopropylethylamine or
`pentamethylpiperidine when X is CF3Sb3•
`
`25
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 007
`
`

`
`CA 02124259 2007-01-31
`
`-6-
`
`A preferred compound Is 40-Q-(2-hydroxy)ethyl rapamycln (hereinafter compound A)
`as disclosed in W0/1994/009010.
`
`Examples of compounds of the FK 506 class are those mentioned above. They
`include for example FK 506, ascomycin and other naturally occuring compounds.
`They Include also synthetic analogues.
`
`5
`
`A preferred compound of the FK 506 class is disclosed in EP 427 680, e.g.
`Example 66a.
`Other preferred compounds are disclosed in EP 465 426.
`
`10
`
`15
`
`The hydrophilic phase may be selected from Transcutol (which has the formula
`C2H8-(0-(CH2) 2kOH), Glycofurol (also known as tetrahydrofurfuryl alcohol
`polyethylene glycol ether) and 1 ,2-propylene glycol, or mixtures thereof, and is
`preferably 1,2-propylene glycol. The hydrophilic phase may include further
`hydrophilic co-components, for example lower alkanols such as ethanol. These co(cid:173)
`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, encapsulated form. This is because storage
`characteristics are Improved, in particular the risk of rapamycln precipitation
`following encapsulation procedures Is reduced. Thus the shelf life stability may be
`20
`extended by employing ethanol or some other such co-component as an additional
`_________ ··-----------~ng!~~~~nt _c:>!_!!l_~~¥~!OP~i~~P~iil~~·-'fll~~than~l-~Ci¥~mpris!_Q!~60 o~ by ~eight .
`of the hydrophilic phase; preferably 20 to 55% by weight and more preferably about
`40 to 50 % by weight. Small quantities of Rquld ·polyethylene glycols may also be
`Included in the hydrophilic phase.
`
`25
`
`Preferred lipophilic phase components are medium chain fatty acid triglycerides,
`mixed mono-, di-, tri-glycerides, and transesterified ethoxylated vegetable oils.
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 008
`
`

`
`CA 02124259 2007-01-31
`
`-7-
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`Suitable medium chain fatty acid trfglyeerides are those known and ·commercially
`available under the trade marks Miglyol, Captex, Myritol, Capmul, Captex, Neobee
`and Mazol; Miglyol 812 being the most preferred. These trfglycerides are described
`In Fiedler, H. P. "Lexikon der Hllfsstoffe tor Pharmazie, Kosmetik und angrenzende
`Gebiete", Editlo Cantor, D-7960 Aulendorf, 3rd revised and expanded edition
`(1989),
`
`· The mixed mono-, di-, tri-glycerides preferably comprise mixtures of 0 12•20 fatty acid
`mono-, di- and tri-glycerides, especially mixed C1s.18 fatty acid mono-, di- and
`triglycerides. 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 predominantly comprised of unsaturated fatty acid residues; In
`particular 0 18 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 0 18 unsaturated fatty acid (for example linolenic, linoleic
`and oleic acid) mono-, di- and trl-glycerides. Suitably the mixed mono-, di-,
`tri-glycerides comprise less than 20%, for example about 15% or 1 0% 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 predominantly comprised of
`mono- and di-glycerides; for example mono- and dl-glycerides comprise at least
`50%, more preferably at least 700/o based on the total weight of the fipophillc phase.
`More preferably, the mono- and di-glycerides comprise at least 75% (for example
`
`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.
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`5
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`10
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`15
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`20
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`25
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`Par Pharm., Inc.
`Exhibit 1005
`Page 009
`
`

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`'W'r-b 1
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`k
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`---.
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`212d259
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`-8-
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`Case 1 00-8039
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`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-glycerldes. More
`
`preferably from about 40 to about 55% (for example 48 to 50%) diglycerides are
`present.
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`5
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`The triglycerldes suitably comprise at least 5% but less than about 25 %, based on
`
`the total weight of the lipophilic phase, of the mixed mono-, di-, trl-glycerides. More
`
`preferably from about 7.5 to about 15% (for example from about 9 to 12%}
`triglycerldes are present.
`
`The mixed mono-, dl·, tri-glycerides may be prepared by admixture of Individual
`
`10
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`mono-, di- or tri-glycerides in appropriate relative proportion. Conveniently however
`
`they comprise transesterificatlon 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 transesterification products are generally obtained by heating the selected
`vegetable oil with glycerol, at high temperature in the presence of an appropriate
`
`15
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`catalyst under an inert atmosphere with continuous agitation (for example In a
`
`stainless steel reactor) to effect trans-esterification or glycerolysis. In addition to
`their mono-, di- and tri-glyceride components, the transesterification products also
`
`gener~lly comprise minor amounts of free glycerol. The amount of free glycerol
`present is preferably less than 1 0%, more preferably less than 5%, most preferably
`
`20
`
`about 1 or 2% by weight based on the total weight of free glycerol plus mono-, dl(cid:173)
`and trl-glycerldes.
`
`Preferably some of the glycerol is first removed to give a "substantially glycerol free
`
`batch" when soft gelatine capsules are to be made.
`
`25
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`Trans-esterification products of corn oil and glycerol provide particularly suitable
`mixed mono-, di-, and tri-glycerides. An example of a suitable mixed glyceride
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 010
`
`

`
`t'tW
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`X't
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`1
`
`net& w--- ,. rwu-.-.--·
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`'tt'·
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`
`CA 02124259 2007-01-31
`
`-9-
`
`(
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`5
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`1 0
`
`. 15
`
`product Is the trans-esterification product commercially available under the trade
`mark 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-, dl- and trl-glycerldes (com oil Hself 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 Gattefosse, of 36, Chemin de Ganas, P.O.Box- 603, 69804
`Ssint-Priest, Cedex (France)] are: up to 10% (typtcally 3.9 to 4.9% or, In
`"substantially glycerol free" batches, about 0.2%) free glycerol; about 35% (typically
`30 to 40% or, In "substantially glycerol free" batches, about 32 to 36%, for exarnple
`about 36%) mono-glycerides; about 500k (or •. ln "substantially glycerol free" batches
`about 46 to 48%) dl-glycerides; about 10% (or, In "substantially glycerol free"
`batches, about 12 to 15%) trl-glycerides: and about 1% free oleic acid.
`
`Further physical characteristics for MAISI~E are: an acid value of maximum about
`2, an Iodine no. of abo~ 85 to 105, a sapc:;nlflcation no. of.about 150 to 175
`(Redler "Lexlkon dar 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.
`
`20
`
`It Is especlally preferred that the mixed mono-, di-, and tri-glycerfdes are clear and
`remain clear for more than 20 days upon_ storage at temperatures of 20°0 to 25°0.
`~--- ·--c----- ··---AiSo, asampie-ofttie-mtxEifmo~-(jf-~-aridtrliityceriCfes:-WiliCt111as_6_een-kepTtn a.
`refrigerator at about between 2 and soc for 24 hours and then held at room
`temperature for 1 . hour, should b~ clear.
`
`25
`
`Preferably the mono-, di-, trl-glycerides have a low saturated fatty acid content.
`Mixed mono-, dl-, tri-glycerides meeting these requirements may. be obtained from
`commercially available products by se-paration techniques as known In the art (for
`example freezing procedures coupled with s~paratlon techniques such as
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 011
`
`

`
`'""'""
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`212d2S9
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`-1 0-
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`Case 1 00-8039
`
`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 <1 0%, or <5%) by weight
`
`based on the total weight of the lipophilic phase. A reduction of the content of
`
`5
`
`saturated fatty acid component in the mono-glyceride fraction may be observed
`after being subjected to the separation technique. A suitable process is described
`In WO 93/09211.
`
`The mixed mono-, dl-, tri-glycerides thus preferably contain lesser quantities of
`
`saturated fatty acids (e.g. palmitic and stearic acids) and relatively greater
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`10
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`quantities of unsaturated fatty acids (e.g. oleic and linoleic acids) than the starting
`
`material.
`
`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%
`
`dl-glycerides and 12 to 20% tri-glycerides, by weight based on the total weight of
`
`15
`
`the lipophilic phase. Further characteristics include the following:
`
`Fatty acid content
`
`Methyllinoleate 53 to 63%,
`
`(as determined as the methyl ester by Methyl oleate 24 to 34%,
`
`chromatography)
`
`Methyl linolenate 0 to 3%
`
`Methyl arachate 0 to 3%,
`
`Methyl palmitate 6 to 12%,
`
`Methyl stearate 1 to 3%
`
`--Relatlve-Benslty-~---------------------- - -0;94-to-0;-96------- -- --------------------
`
`20
`
`Hydroxyl Value
`
`Iodine Value
`
`Peroxide Value
`
`Free Glycerol
`
`140 to 210
`
`110 to 20
`
`<4.0
`
`<1.0
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 012
`
`

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`CA 02124259 2007-01-31
`
`-11-
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`Saponification no
`
`Acid value
`
`about 150 to 185
`
`max. about 2
`
`5
`
`10
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`Mixed mono-, di-, trl-glycerldes complying with these characteristics are referred to
`In this specification as "refined glycerol-transesterifled com oils". The "refined
`glycerol-transesterlfied corn oils" have the advantage of remaining stable for a long
`time.
`
`The llpophiRc phase may aHernatlvely comprise suitable transesterified 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,
`sunflower off, safflower oil and palm oil, or mixtures thereof) with polyethylene
`glycols that have an average molecular weight of from 200 to 800, In the presenw
`of an appropriate catalyst. These procedures are known and an example is
`described In US Patent 3 288 824. Transesterlfled ethoxylated com oil Is
`particularly preferred.
`
`15
`
`Transesterified ethoxylated vegetable oils are known and are; commercially available
`under the trade mark LABRAFIL (H. Redler, Jo.c...m, vol 2, page 707). Examples
`are LABRAFIL M 2125 CS (obtained from com oil and having an acid number of
`less than about 2, a saponlfl<4itlon 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 saponification number of 145 to
`20
`. -~~-----··- ~---------·----~--~-,~-----~-~--~--~~--~-------~~--~"----- --~-- -------"----~-------- ---------- ·~-
`175 and an iodine number of 60 to 90}. LABRAFIL M 2130 CS (which Is a
`transesterificatlon 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
`saponification number of 185 to 200 and an iodine number of less than about 3)
`may also be used The preferred transesterifled ethoxylated vegetable oil is
`LABRAFJL M 2125 CS which can be obtained, for.example,.from Gattefosse, Saint(cid:173)
`Priest Cedex, France.
`
`25
`
`-
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 013
`
`

`
`met
`
`tt¥sex
`
`, -wur
`
`CA 02124259 2007-01-31
`
`-12-
`
`(
`
`Examples of suitable surtactants are:
`
`5
`
`1 0
`
`15
`
`20
`
`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 products. Various such surfactants
`are commercially available. The polyethyleneglycol-hydrogenated castor oils
`available under the trade mark CREMOPHOR are especially suitable.
`Particularly suitable are CREMOPHOR RH 40, which has a saponification
`number of about 50 to 60, an acid number less than about 1 , a water content
`'( Ascher) less than about 2o/o, an n0 fJ(J of about 1.453 to 1.457 and an HLB of
`about 14 to 16; and CREMOPHOR RH 60, which has a saponification
`number of about 40 to 50, an acid number less than about 1, an iodine
`number of less than about 1, a water content (Ascher) of about 4.5 to 5.5%,
`25 of about 1.453 to 1.457 and an HLB of about 15 to 17. An especially
`an n0
`preferred product of this class is CREMOPHOR RH40. Also suHable 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 saponification number of about 65 to 70, an acid number of
`about 2, an Iodine number of about 28 to 32 and an n0
`25 of about 1.471.
`Similar or identical products which may also be used are available under the
`trade marks NIKKOL (e.g. NIKKOL HCQ-40 and HC0-60), MAPEG (e.g.
`MAPEG C0-40h), INCROCAS (e.g. INCROCAS 40), and TAGAT (e.g.
`TAGAT RH 40). These surfactants are further described in Redler Joe. cit ..
`
`li)
`
`25
`
`Polyoxyethylene-sorbHan-fatty acid esters, for example mono- and tri-lauryl,
`palmityl, stearyl and oleyl esters of the type known and commercially
`available under the trade mark TWEEN (Fiedler; Joc.cit. p.1300-1304)
`including the products lWEEN
`2.Q [polyoxyethylene(20)sorbitarimonolaurate),
`2.1 [polyoxyethylene( 4 )sorbltanmonolaurate ].
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 014
`
`

`
`fj(
`
`r «fB«'f
`
`--
`
`CA 02124259 2007-01-31
`
`•· m wm
`
`><
`
`WtNfS'rtt?'H . Oz-tt
`
`-13-
`
`~ [polyoxyethylene(20)sorbitanmonopalmltate],
`.6Q [polyoxyethylene(20)sorbltanmonostearate],
`.6.§ [polyoxyethylene(20)sorbitantristearate ],
`ml [polyoxyethylene(20)sorbitanmonooleate],
`1U [polyoxyethylene(5)sorbltanmonooleate],
`1m [polyoxyethylene(20)sorbitantrioleate].
`
`Especially preferred products of this class are lWEEN 40 and TWEEN 80.
`
`Ill)
`
`Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid
`esters of the type known and commercially available under the trade name
`MYRJ (Redler, Joe. cit., .2. p.834-835). An especially preferred product of this
`class Is MYRJ 52 haVing a 0 25 of about 1.1., a melting point of about 40 to
`440C, an HLB value of about 16.9.1 an ~cid value of about 0 to 1 and a
`saponification no. of about 25 to 35.
`
`5
`
`10
`
`iv)
`
`15
`
`Polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, for
`example of the type known and commercially available under the trade
`· marks PLURONIC, EMKAL YX 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.
`
`- . ·-~- -·--~----- -------~»---------------~------------
`
`20
`
`v)
`
`Dloctylsulfosucclnate or di-[2-ethylhexyij-succinate (Fiedler, Joe. 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 dl-fatty acid esters such as propylene glycol
`dicaprylate (also known and commercially available under the trade mar1<
`
`25
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 015
`
`

`
`2124259
`
`-14-
`
`Case 1 00-8039
`
`·.·.·.
`
`MIGLYOL 840}, propylene glycol dilaurate, propylene glycol hydroxystearate,
`propylene glycol isostearate, propylene glycol laurate, propylene glycol
`ricinoleate, propylene glycol stearate and so forth (Redler, Joe. cit., .2. p.
`808-809).
`
`5
`
`It will also be appreciated that the components of the carrier medium may contain
`unreacted starting materials, e.g. polyethylene glycol.
`
`The surfactant selected preferably has an HLB of at least 1 0.
`
`1 0
`
`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 addition to water, of providing microemulsions
`having an average particle size of <1 .500A and stable over periods in excess of 24
`hours.
`
`15
`
`The microemulsion preconcentrate compositions 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.
`
`Altern~tlvely 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
`~- ----20---shelf-life-stabHity~of--up-to--three--years;--and-'9ven-tonger:-, __________ -----"-----------------------"---------- ·---- -------------- ~-~-~-----~- --
`
`· ..
`
`-~·
`
`·-
`
`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 sweetening
`
`25
`
`Par Pharm., Inc.
`Exhibit 1005
`Page 016
`
`

`
`21212 ~) 9
`
`-15-
`
`Case 1 00-8039
`
`or flavoring 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
`E).
`
`The pharmaceutical composition may also include one or more other
`immunosuppressants such as, for example, a cyclosporin or if a rapamycin is
`
`5
`
`present a FK 506 compound as described above. Cyclosporins comprise a class of
`cyclic, poly-N-methylated undecapeptides, generally possessing
`
`Immunosuppressive, anti-Inflammatory, anti-viral and/or anti-parasitic activity, each
`
`to a greater or lesser degree. The first of the cyclosporlns to be identified was the
`fungal metabolite Cyclosporin A, or Ciclosporlne, and its structure is given in The
`
`10
`
`Merck Index, 11th Edition; Merck & Co., Inc.; Rahway, New Jersey, USA (1989)
`under listing 2759. Later cyclosporins to be Identified are cyclosporins B, C, D and
`G which are also listed in the Merck h1dex under listing 2759. A large number of
`synthetic analogs are also known and representative examples are disclosed in EP
`
`15
`
`296 122, EP 484 281 and GB 2222770. These compounds are termed collectively
`"cyclosporlns" in this specification.
`
`The pharmaceutical composition exhibits especially advantageous properties when
`administered orally; for example in terms of consistency and high level of
`bioavallability obtained in standard bioavailabillty trials, e.g. 2 to 4 times higher than
`emulsions. These trials are performed in animals or healthy volunteers using HPLC
`or a specific or nonspecific 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
`
`20
`
`·-~-----~--admlnlstered~p;o;--torats-and1hesurprising1y-higlleffi8X-valoesotbetween2670·and---
`
`3400 ng/ml are detected by ELISA using a specific monoclonal antibody. Also, in
`
`25
`
`the test described In Example 4, an emulsion preconcentrate and a mlcroemulsion
`
`preconcentra