PCT
`WORLD INTELLECfUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCn
`wo 97103654
`
`(51) International Patent Classification 6 :
`A61K 9/14
`
`A2
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`6 February 1997 (06.02.97)
`
`(21) International Application Number:
`
`PCTIEP96/03066
`
`(74) Common Representative: SANDOZ LTD.; Patents & Trade(cid:173)
`marks Div., Lichtstrasse 35, CH-4002 Basle (CH).
`
`(22) International Filing Date:
`
`12 July 1996 (12.07.96)
`
`(30) Priority Data:
`9514397.0
`9515025.6
`
`14 July 1995 (14.07.95)
`21 July 1995 (21.07.95)
`
`GB
`GB
`
`(71) Applicant (for all designated States except AT DE US): SAN(cid:173)
`DOZ LTD. [CHICH]; Lichtstrasse 35, CH-4002 Basle (CH).
`
`(71) Applicant (for DE only):
`SANDOZ-PATENT-GMBH
`[DE/DE]; Humboldtstrasse 3, D-79539 LOrrach (DE).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BB, BG, BR, BY,
`Cf.., CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IL,
`IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ,
`VN, ARIPO patent (KE, LS, MW, SD, SZ, UG), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT,
`LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI,
`CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (for AT only): SANDOZ-ERFINDUNGEN VER-
`WALTUNGSGESELLSCHAFT M.B.H. [AT/AT]; Brunner
`Strasse 59, A-1230 Vienna (An.
`
`Published
`Without international search report and to be republished
`upon receipt of that report.
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): GUITARD, Patrice
`[FRIFR]; 13, rue Bellevue, F-68220 Hegenheim (FR).
`HAEBERLIN, Barbara [CHICH]; Haselrain 77, CH-4125
`Riehen (CH). LINK, Rainer [DE/DE]; Zum Urwaldele 2,
`D-79219 Staufen (DE). RICHTER, Friedrich [DE/DE];
`Rebgasse 17, D-79639 Grenzach-Wyhlen (DE).
`
`(54) Title: PHARMACEUTICAL COMPOSITIONS
`
`(57) Abstract
`
`A pharmaceutical composition in the form of a solid dispersion comprising a macrolide, e.g. a rapamycin or an ascomycin, and a
`carrier medium.
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 001
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI' on the front pages of pamphlets publishing international
`applications under the PCI'.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cs
`cz
`DE
`DK
`EE
`ES
`FI
`FR
`GA
`
`Annenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Gennany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LR
`LT
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`MR
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TT
`UA
`UG
`us
`uz
`VN
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`VietNam
`
`-~
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 002
`
`

`
`W097/03654
`
`PCT/EP96/03066
`
`Pharmaceutical compositions
`
`This invention relates to oral pharmaceutical comp<;>sitions comprising a macrolide, e.g. a
`
`rapamycin or an ascomycin, in a solid dispersion.
`
`5 Rapamycin is an immunosuppressive lactam macrolide produceable, for example by
`
`Streptomyces hygroscopicus. The structure of rapamycin is given in Kesseler, H., et al.;
`
`1993; Helv. Chim. Acta; 76: 117. Rapamycin is an extremely potent
`
`immunosuppressant and has also been shown to have antitumor and antifungal activity. Its
`
`utility as a pharmaceutical, however, is restricted by its very low and variable
`
`10 bioavailability. Moreover, rapamycin is highly insoluble in aqueous media, e.g. water,
`
`making it difficult to formulate stable galenic compositions. Numerous derivatives of
`
`rapamycin are known. Certain 16-0-substituted rapamycins are disclosed in WO
`
`94/02136, the contents of which are incorporated herein by reference. 40-0-substituted
`
`rapamycins are described in, e.g., in US 5 258 389 and WO 94/09010 (0-aryl and 0-alkyl
`
`15
`
`rapamycins); WO 92/05179 (carboxylic acid esters), US 5 118 677 (amide esters), US 5
`
`118 678 (carbamates), US 5 100 883 (fluorinated esters), US 5 151 413 (acetals), US 5
`
`120 842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO
`
`94/02136 (methoxy derivatives), WO 94/02385 and WO 95114023 (alkenyl derivatives) all
`
`of which are incorporated herein by reference. 32-0-dihydro or substituted rapamycin are
`
`20 described, e.g., in US 5 256 790, incorporated herein by reference.
`
`Further rapamycin derivatives are described in PCT application number EP96/02441, for
`
`example 32-deoxorapamycin as described in Example 1, and 16-pent-2-ynyloxy-32(S)(cid:173)
`
`dihydrorapamycin as described in Examples 2 and 3. The contents of PCT application
`
`number EP96/02441 are incorporated herein by reference.
`
`25 Rapamycin and its structurally similar analogues and derivatives are termed collectively
`
`herein as "rapamycins".
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 003
`
`

`
`W097/03654
`
`PCT/EP96/03066
`
`-2-
`
`On oral administration to humans, solid rapamycins, e.g. rapamycin, may not be absorbed
`
`to any significant extent into the bloodstream. Simple mixtures are known for rapamycins,
`
`e.g. rapamycin, with conventional pharmaceutical excipients; however, disadvantages
`
`encountered with these compositions include unpredictable dissolution rates, irregular
`
`5 bioavailability profiles, and instability. To date th~re is no conveniently administrable oral
`
`solid formulation available for rapamycin or a derivative thereof.
`
`Accordingly, in one aspect, this invention provides a pharmaceutical composition in the
`
`form of a solid dispersion comprising a rapamycin and a carrier medium.
`
`The compositions of this invention provide a high bioavailability of drug substance, are
`
`10
`
`convenient to administer, and are stable.
`
`The rapamycin used in the compositions of this invention may be any rapamycin or
`
`derivative thereof, for example as disclosed above or in the above-mentioned patent
`
`applications.
`
`Thus the rapamycin used in the solid dispersion compositions of this invention may be
`
`15
`
`rapamycin or an 0-substituted derivative in which the hydroxyl group on the cyclohexyl
`ring of rapamycin is replaced by -OR1 in which R1 is hydroxyalkyl, hydroxyalkoxyalkyl,
`acylaminoalkyl and aminoalkyl; e.g. as described in W094/09010, for example 40-0-(2-
`
`hydroxy )ethy 1-rapamycin, 40-0-(3-hydroxy )propyl-rapamycin, 40-0-[2-(2-
`
`hydroxy)ethoxy]ethyl-rapamycin and 40-0-(2-acetaminoethyl)-rapamycin. The rapamycin .
`
`20 derivative may be a 26- or 28-substituted derivative.
`
`Preferred rapamycins for use in the solid dispersion compositions of this invention include
`
`rapamycin, 40-0-(2-hydroxy)ethyl rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-
`
`32(8)-dihydroraparnycin. A more preferred rapamycin is 40-0-(2-hydroxy)ethyl rapamycin
`
`(hereinafter referred to as compound X).
`
`25 Numbering of raparnycin derivatives as used herein refers to the structure disclosed as
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 004
`
`

`
`wo 97/03654
`
`PCT/EP96/03066
`
`-3-
`
`Formula A at page 4 of published PCf application WO 96113273, the contents of which
`
`are incorporated herein by reference.
`
`The term solid dispersion as used herein is understood to mean a co-precipitate of the
`
`rapamycin, e.g. 40-0-(2-hydroxy)ethyl rapamycin O! rapamycin, with the carrier medium.
`In the solid dispersion, the rapamycin is in amorphous or substantially amorphous form
`
`5
`
`and is physically bound to the carrier medium.
`
`Compositions of this invention may be administered in any convenient form, for example
`
`tablet, capsule, granule or powder form, e.g. in a sachet.
`
`The rapamycin may be present in the composition in an amount of about 0.01 to about 30-
`
`10 weight-% based on the weight of the composition(% w/w}, and preferably in an amount of
`
`1 to 20 % w/w based on the total weight of the composition.
`
`The carrier medium is present in an amount of up to 99.99% by weight, for example 10 to
`
`95 wt-%, based on the total weight of the composition.
`
`In one embodiment the carrier medium comprises a water-soluble polymer, preferably a
`
`15
`
`cellulose derivative such as hydroxypropylmethylcellulose (HPMC),
`
`hydroxypropylmethylcellulose phthalate, or polyvinylpyrrrolidone (PVP). Good results
`
`may be obtained using HPMC with a low apparent dynamic viscosity, e.g. below 100 cps
`
`as measured at 20"C for a 2 % by weight aqueous solution, e.g below 50 cps, preferably
`
`below 20 cps, for example HPMC 3 cps. HPMC is well-known and described, for
`
`20
`
`example, in the Handbook of Pharmaceutical Excipients, Second Edition, pub.
`
`Pharmaceutical Society of Great Britain and American Pharmaceutical Association, 1994,
`
`p.229 to 232, the contents of which are incorporated herein by reference. HPMC,
`
`including HPMC 3cps, is available commercially under the trade name Pharmacoat 603
`
`from the Shinetsu company.
`
`25 PVP is available, for example, under the name Povidone (Handbook of Pharmaceutical
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 005
`
`

`
`W097/03654
`
`PCT/EP96/03066
`
`-4-
`
`Excipients), and a PVP having an average molecular weight between about 8,000 and
`
`about 50,000 Daltons is preferred.
`
`In another embodiment the carrier medium comprises
`
`hydroxypropylcellulose (HPC) or a derivatiye thereof. Examples of HPC
`
`5 derivatives include those having low dynamic viscosity in aqueous media, e.g. water, e.g
`
`below about 400 cps, e.g below 150 cps as measured in a 2% aqueous solution at 25°C.
`
`Preferred HPC derivatives have a low degree of substitution, and an average molecular
`
`weight below about 200,000 Daltons, e.g. between 50,000 and 150,000 Daltons. Examples
`
`of HPC available commercially include Klucel LF, Klucel EF and Klucel JF from the
`
`10 Aqualon company; and Nisso HPC-L available from Nippon Soda Ltd;
`
`a polyethylene glycol (PEG). Examples include PEGs having an average molecular
`
`weight between 1000 and 9000 Daltons, e.g. between about 1800 and 7000, for example
`
`PEG 2000, PEG 4000 or PEG 6000 (Handbook of Pharmaceutical Excipients);
`
`a saturated polyglycolised glyceride, available for example under the trade mark
`
`15 Gelucir, e.g. Gelucir 44/14, 53110, 50/13, 42112, or 35/10 from the Gattefosse company; or
`
`a cyclodextrin, for example a ~-cyclodextrin or an a-cyclodextrin. Examples of
`
`suitable ~-cyclodextrins include methyl-~-cyclodextrin; dimethyl-~-cyclodextrin;
`
`hydroxypropyl-~-cyclodextrin; glycosyl-~-cyclodextrin; maltosyl-~-cyclodextrin; sulfo-~­
`
`cyclodextrin; sulfo-alkylethers of ~-cyclodextrin, e.g. sulfo-C 1-4-alkyl ethers. Examples of
`a-cyclodextrins include glucosyl-a-cyclodextrin and maltosyl-a-cyclodextrin.
`
`20
`
`The carrier medium may further comprise a water-soluble or water-insoluble saccharose or
`
`other acceptable carrier or filler such as lactose, or microcrystalline cellulose. The flller, if
`
`present, is generally in an amount of up to about 30% by weight, e.g. 0.5 to 20 wt-%,
`
`preferably, from about 5 to about 15% by weight of the composition. Microcrystalline
`
`..
`
`25
`
`cellulose is available commercially under the trade name A vicel, for example from FMC
`
`Corporation.
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 006
`
`

`
`W097/03654
`
`PCT/EP96/03066
`
`-5-
`
`The carrier medium may further comprise one or more surfactants, for example a non(cid:173)
`
`ionic, ionic, anionic or amphoteric surfactant. Examples of suitable surfactants include
`
`polyoxyethylene-polyoxypropylene co-polymers and block co-polymers known, for
`
`example, under the trade names Pluronic or Polox~er, e.g. as described in Fiedler, H. P.
`
`5
`
`"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. A preferred polyoxyethylene-polyoxypropylene
`
`block polymer is Poloxamer 188 available from the BASF company;
`
`ethoxylated cholesterins known, for example, under the trade name Solulan, for
`
`10
`
`example Sol ulan C24 commercially available from the Amerchol company;
`
`vitamin derivatives, e.g. vitamin E derivatives such as tocopherol polyethylene
`
`glycol succinate (TPGS) available from the Eastman company;
`
`sodium dodecylsulfate or sodium laurylsulfate;
`
`a bile acid or salt thereof, for example cholic acid, glycolic acid or a salt, e.g.
`
`15
`
`sodium cholate; or
`
`lecithin.
`
`If present in the compositions of this invention, the surfactant(s) is generally in an amount
`
`of up to about 20%, for example 1 to 15% by weight.
`
`One or more disintegrants may be included in the compositions of this invention.
`
`,.
`
`20 Examples of disintegrants include Polyplasdone (Handbook of Pharmaceutical Excipients)
`
`available commercially from the ISP company; sodium starch glycolate available
`
`commercially from the Generichem company; and crosscarmelose sodium available under
`
`the trade mark Ac-di-sol from FMC Corporation. One or more lubricants, for example
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 007
`
`

`
`wo 97/03654
`
`PCT/EP96/03066
`
`-6-
`
`magnesium stearate or colloidal silicon dioxide, may further be included in the composition
`
`of this invention in an amount of up to about 5 weight%, e.g. 0.5 to 2wt-%, based on the
`
`weight of the composition.
`
`It may be advantageous to include one or more fl~vouring agents in the compositions of
`
`5
`
`this invention.
`
`The present applicants have obtained good results using surfactant-free rapamycin
`
`compositions. In another aspect, therefore, this invention provides a surfactant-free solid
`
`dispersion composition comprising a rapamycin as described herein.
`
`Antioxidants and/or stabilisers may be included in the compositions of this invention in an
`
`10
`
`amount of up to about 1 % by weight, for example between 0.05 and 0.5 % by weight.
`
`Examples of antioxidants include butylated hydroxytoluene, DL-cx-tocopherol, propyl
`
`gallate, ascobyl palmitate and fumaric acid. Malonic acid is an appropriate stabiliser.
`
`In one embodiment of this invention, the composition comprises up to 30% by weight, e.g.
`
`1 to 20 wt-%, 40-0-(2-hydroxy)ethyl rapamycin, and up to 95 %, e.g. 30 to 90%, HPMC
`
`15 by weight.
`
`The weight ratio of the rapamycin to carrier medium in the compositions of this invention
`
`is generally no more than 1:3, preferably less than 1:4.
`
`In another aspect, this invention provides a process for preparing a solid dispersion
`
`composition as described herein.
`
`20
`
`In one embodiment the compositions of this invention may be obtained by dissolving or
`
`suspending the rapamycin and carrier medium in a solvent or solvent mixture. The solvent
`
`may be a single solvent or mixture of solvents, and the order of dissolution and suspension
`
`of the rapamycin with the carrier medium in the solvent may be varied. Solvents suitable
`
`for use in preparing solid dispersion compositions of this invention may be organic
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 008
`
`

`
`W097/03654
`
`PCT/EP96/03066
`
`-7-
`
`solvents such as an alcohol, for example methanol, ethanol, or isopropanol; an ester, e.g.
`
`ethylacetate; an ether, e.g. diethyl ether; a ketone, e.g. acetone; or a halogenated
`
`hydrocarbon, e.g. dichloroethane. A convenient solvent mixture is an ethanol/acetone
`
`mixture having a weight ratio of ethanol to acetone of between about 1: 10 to about 10: 1,
`
`5
`
`for example 1:5 to 5:1.
`
`Typically the rapamycin and carrier medium are present in a ratio by weight with the
`
`solvent of 1:0.1 to 1:20. The solvent may be evaporated and the rapamycin co-precipitated
`
`with carrier medium. The resulting residue may be dried, for example under reduced
`
`pressure, sieved and milled. The milled dispersion may be combined with other excipients
`
`10
`
`and, for example, compressed as a tablet, or filled into sachets or gelatin capsules.
`
`In another embodiment, the solid dispersion compositions may be prepared by melting the
`
`carrier medium to form a melt, and combining the melt with the rapamycin, e.g. by
`
`stirring, optionally in the presence of a solvent or solvent mixture as described herein.
`
`Alternatively the solid dispersions of this invention may be prepared by spray drying
`
`15
`
`techniques as described, for example, in Theory and Practice of Industrial Pharmacy,
`
`Lachmann et al., 1986. A suspension as formed above is dispersed through a nozzle into a
`chamber maintained at, for example, 20 to so·c. The solvent is evaporated on passing
`through the nozzle, and finely dispersed particles are collected.
`
`The compositions of this invention, after milling, typically have a mean particle size of
`
`20
`
`less than about 0.5mm, for example less than about 350 J.liil, e.g. about 100 to about 300
`
`J.liil.
`
`The oral compositions of this invention are useful for the known indications of the
`
`rapamycin, e.g. the following conditions:
`
`a)
`
`Treatment and prevention of organ or tissue allo- or xeno-transplant
`
`25
`
`rejection, e.g. for the treatment of recipients of e.g. heart, lung, combined heart-lung, liver,
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 009
`
`

`
`W097103654
`
`PCT/EP96/03066
`
`-8-
`
`kidney, pancreatic, skin or corneal transplants. They are also indicated for the prevention
`
`of graft-versus-host disease, such as following bone marrow transplantation.
`
`b)
`
`Treatment and prevention of autoimmune disease and of inflammatory
`
`conditions, in particular inflammatory conditions with an etiology including an autoimmune
`
`5
`
`component such as arthritis (for example rheumato~d arthritis, arthritis chronica progred(cid:173)
`
`iente and arthritis deformans) and rheumatic diseases. Specific autoimmune diseases for
`
`which the compounds of the invention may be employed include, autoimmune
`
`hematological disorders (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell
`
`anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis,
`
`10
`
`sclerodoma, Wegener 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
`
`ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis,
`
`juvenile diabetes (diabetes mellitus type 1), uveitis (anterior and posterior),
`
`15 keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic
`
`arthritis, glomerulonephritis (with and without nephrotic syndrome, e.g. including
`
`idiopathic nephrotic syndrome or minimal change nephropathy) and juvenile
`
`dermatomyositis.
`
`c)
`
`d)
`
`20
`
`Treatment and prevention of asthma.
`
`Treatment of multi-drug resistance (MDR). MDR is particularly problematic
`
`in cancer patients and AIDS patients who will not respond to conventional chemotherapy
`
`because the medication is pumped out of the cells by Pgp. The compositions are therefore
`
`useful for enhancing the efficacy of other chemotherapeutic agents in the treatment and
`
`control of multidrug resistant conditions such as multidrug resistant cancer or multidrug
`
`25
`
`resistant AIDS.
`
`e)
`
`Treatment of proliferative disorders, e.g. tumors, hyperproliferative skin
`
`disorder and the like.
`
`f)
`
`g)
`
`Treatment of fungal infections.
`
`Treatment and prevention of inflammation, especially in potentiating the
`
`30
`
`action of steroids.
`
`h)
`
`Treatment and prevention of infection, especially infection by pathogens
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 010
`
`

`
`wo 97/03654
`
`PCT/EP96/03066
`
`-9-
`
`having Mip or Mip-like factors.
`
`i)
`
`Treatment of overdoses of FK-506 and other macrophilin binding
`
`immunosuppressants.
`
`Where the pharmaceutical composition of this inve~tion is in unit dosage form, e.g. as a
`
`5
`
`tablet, capsule, granules or powder, each unit dosage will suitably contain between 1mg
`
`and 100 mg of the drug substance, more preferably between 10 and 50 mg; for example
`
`15, 20, 25, or 50 mg. 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.
`
`The exact amount of the compositions to be administered depends on several factors, for
`
`10
`
`example the desired duration of treatment and the rate of release of the rapamycin.
`
`The utility of the pharmaceutical compositions can be observed in standard clinical tests in,
`
`for example, known indications of active agent dosages giving equivalent blood levels of
`
`active agent; for example using dosages in the range of 1 mg to 1000 mg, e.g. 5mg to
`
`lOOmg, of active agent per day for a 75 kilogram adult and in standard animal models.
`
`15 The increased bioavailability of the drug substance provided by the compositions can be
`
`observed in standard animal tests and in clinical trials.
`
`The dosage form used, e.g. a tablet, may be coated, for example using an enteric coating.
`
`Suitable coatings may comprise cellulose acetate phthalate; hydroxypropylmethylcellulose
`
`phthalate; a polymethyacrylic acid copolymer, e.g. Eudragit L, S; or
`
`20 hydroxypropylmethylcellulose succinate.
`
`The rapamycin used in the compositions of this invention, e.g. 40-0-(2-hydroxy)ethyl
`
`rapamycin or rapamycin, may be in crystalline or amorphous form prior to formation of
`
`the solid dispersion. An advantage, therefore, of this invention is that the rapamycin need
`
`not be crystalline. Thus the rapamycin may be used directly in combination, for example
`
`25 with a solvent, and does not have to be isolated in advance. Another advantage of the
`
`invention is that dissolution rates of the solid dispersion are higher than dissolution rates
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 011
`
`

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`W097/03654
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`PCT/EP96/03066
`
`-10-
`
`found for a crystalline rapamycin or an amorphous rapamycin in a simple mixture.
`
`In another aspect, this invention provides a pharmaceutical composition in the form of a
`
`solid dispersion comprising an ascomycin and a carrier medium.
`
`,
`
`Examples of suitable ascomycins for use in the solid dispersion compositions of this
`
`5
`
`invention include ascomycin or a derivative thereof, e.g. 33-epi-chloro-33-desoxy(cid:173)
`
`ascomycin.
`
`To date there is no conveniently administrable oral solid formulation available for 33-epi(cid:173)
`
`chloro-33-desoxy-ascomycin. In another aspect, therefore, this invention provides a
`
`pharmaceutical composition in the form of a solid dispersion comprising 33-epi-chloro-33-
`
`10 desoxy-ascomycin and a carrier medium.
`
`The compound 33-epi-chloro-33-desoxy-ascomycin is described in published European
`
`application EP 427 680 under Example 66a.
`
`33-epi-chloro-33-desoxy-ascomycin will be referred to hereinafter as Compound Y.
`
`The ascomycin, e.g. compound Y, compositions of this invention provide a high
`
`15
`
`bioavailability of drug substance, are convenient to administer, and are stable.
`
`The ascomycin, e.g. compound Y, may be present in the composition in an amount of
`
`about 0.01 to about 30% w/w, and preferably in an amount of 1 to 20% w/w.
`
`The carrier medium may comprise any of the aforementioned components in amounts by
`
`wt-% as described above. Suitable water-soluble polymers, cyclodextrins and other
`
`20
`
`excipients, e.g. surfactants, for use in the 33-epi-chloro-33-desoxy-ascomycin compositions
`
`r
`
`of this invention are as described above.
`
`In a preferred aspect, this invention provides a surfactant-containing composition
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 012
`
`

`
`wo 97/03654
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`PCT/EP96/03066
`
`-11-
`
`comprising an ascomycin, e.g. compound Y, in the form of a solid dispersion as described
`
`herein .
`
`The weight ratio of the ascomycin, e.g. compound Y, to carrier medium is generally no
`
`more than 1:3, preferably less than 1:4.
`
`..
`
`j
`
`5
`
`The ascomycin, e.g. compound Y, solid dispersion compositions may be prepared in
`
`analogous manner to the processes described above.
`
`The oral compositions of compound Y disclosed herein are useful, for example, in the
`
`treatment of inflammatory and hyperproliferative skin diseases and of cutaneous
`
`manifestations of immunologically-mediated diseases. More specifically, the compositions
`
`10 of this invention are useful as antiinflammatory and as immunosuppressant and
`
`antiproliferative agents for use in the prevention and treatment of inflammatory conditions
`
`and of conditions requiring immunosuppression, such as
`
`a)
`
`the prevention and treatment of
`
`rejection of organ or tissue transplantation, e.g. of heart, kidney, liver, bone
`
`15
`
`marrow and skin,
`
`graft-versus-host disease, such as following bone marrow grafts,
`
`autoimmune diseases such as rheumatoid arthritis, systemic lupus
`
`erythematosus, Hashimoto's thyroidis, multiple sclerosis, Myasthenia gravis,
`
`diabetes type I and uveitis,
`
`20
`
`cutaneous manifestations of immunologically-mediated illnesses;
`
`b)
`
`the treatment of inflammatory and hyperproliferative skin diseases, such as
`
`psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises,
`
`seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid,
`
`Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous
`
`25
`
`eosinophilias, Lupus erythematosus and acne; and
`
`c)
`
`Alopecia areata.
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 013
`
`

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`wo 97/03654
`
`PCT/EP96/03066
`
`-12-
`
`Where the pharmaceutical composition of this invention is in unit dosage form, e.g. as a
`
`tablet, capsule or powder, each unit dosage will suitably contain between 1mg and 100 mg
`
`of the drug substance, more preferably between 10 and 50 mg; for example 15, 20, 25, or
`
`50 mg. Such unit dosage forms are suitable for administration 1 to 5 times daily
`
`5 depending upon the particular purpose of therapy, . the phase of therapy and the like.
`
`In one embodiment of this invention, the composition comprises 30% by weight compound
`
`Y and 70 % by weight HPMC in a dosage of e.g. 10 to 50mg per day for use in, e.g.
`
`psoriasis, atopical dermatitis or contact dermatitis.
`
`The exact amount of the compositions to be administered depends on several factors, for
`
`10
`
`example the desired duration of treatment and the rate of release of compound Y.
`
`The utility of the pharmaceutical compositions containing compound Y can be observed in
`
`standard clinical tests in, for example, known indications of active agent dosages giving
`
`equivalent blood levels of active agent; for example using dosages in the range of 1 mg to
`
`1000 mg of active agent per day for a 75 kilogram adult and in standard animal models.
`
`15 The increased bioavailability of the drug substance provided by the compositions can be
`
`observed in standard animal tests and in clinical trials.
`
`Following is a description by way of example only of solid dispersion compositions of this
`
`invention.
`
`Example 1
`
`20 A solid dispersion composition is prepared containing the following ingredients (in parts
`
`by weight):
`
`Compound X
`
`HPMC 3 cps
`
`Lactose 200 mesh
`
`9.1
`
`81.8
`
`9.1
`
`25 The composition (Form A) is prepared by dissolving the rapamycin and carrier medium in
`
`an ethanol/acetone mixture. Absolute ethanol is used in a 1:1 ratio by weight with the
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 014
`
`

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`W097/03654
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`PCT/EP96/03066
`
`-13-
`
`acetone. The solvents are then evaporated, and the resulting dry residue milled to a fine
`
`powder with mean particle size < 0.5 mm.
`
`1
`
`Example 2
`
`A solid dispersion composition is prepared cont~ng the following ingredients (in parts
`
`5
`
`by weight):
`
`Compound X
`
`HPMC 3 cps
`
`Poloxamer 188 (from BASF)
`
`16.7
`
`66.7
`
`16.7
`
`The composition (Form B) is prepared in analogous manner to that in Example 1.
`
`10 Example 3
`
`A solid dispersion composition is prepared containing the following ingredients (in parts
`
`by weight):
`
`Compound X
`
`HPMC 3 cps
`
`15
`
`TPGS*
`
`16.7
`
`66.7
`
`16.7
`
`The composition (Form C) is prepared in analogous manner to that in Example 1.
`
`*
`
`tocopherol polyethylene glycol succinate
`
`Example 4
`
`A solid dispersion composition is prepared containing the following ingredients (in parts
`
`20 by weight):
`
`Compound X
`
`HPMC 3 cps
`
`Solulan C24
`
`(from Amerchol)
`
`10
`
`80
`
`10
`
`,
`
`The composition (Form D) is prepared in analogous manner to that in Example 1.
`
`25 The above compositions Forms A to D may be formed into tablets, filled into capsules, or
`
`powdered and packaged in sachets.
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 015
`
`

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`W097103654
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`PCT/EP96/03066
`
`-I4-
`
`Pharmacokinetics after administration of 40-0-(2-hydroxy)ethyl rapamycin to rats
`
`a)
`
`Drug administration
`
`0.5 ml aqueous dispersions of the Compound X compositions (corresponding to 4.0 mg
`
`active ingredient/rat) were administered by gastric intubation during a short inhalation
`anaesthesia with a I ml syringe, attached to a polyethylene tube. Six animals were used
`
`5
`
`for each composition Forms A, B, C and D.
`
`b)
`
`Blood sampling
`
`The animals received a permanent cannula into a vena jugularis one day prior to this
`
`experiment. 0.5 ml venous blood (vena jugularis) was collected from each rat and stored
`
`I 0
`
`in 2.5 ml EDT A tubes. The blood samples of 2 animals (1 and 2, 3 and 4, 5 and 6) were
`pooled and stored at -80 ·c until drug analysis. Samples were taken before administration
`and 10 minutes (m), 30m, 60m, 120m, 300m, 480m and 1440m after drug administration.
`
`c)
`
`Bioarialytics
`
`The blood samples were analysed using reversed phase HPLC.
`
`15 Table 1 shows the pharmacokinetic data collected after administration of Compound X to
`
`rats.
`
`t
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 016
`
`

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`W097/03654
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`PCT/EP96/03066
`
`-15-
`
`Table 1
`
`Summary Profiles (averages of 2-3 pools)
`
`blood concentration (ng/ml)
`
`time (h)
`
`FormA
`
`FormB
`
`.,
`
`Forme
`
`FormD
`
`5
`
`0
`
`0.17
`
`0.5
`
`1
`
`2
`
`5
`
`8
`
`24
`
`10
`
`7
`
`118
`
`422
`
`375
`
`277
`
`573
`
`496
`
`93
`
`Cmax (ng/ml)
`
`573
`
`Tmax (hr)
`
`15
`
`AUC 0-Sh
`
`[(ng/ml).h]
`
`5.00
`
`3502
`
`7
`
`117
`
`131
`
`129
`
`82
`
`92
`
`66
`
`30
`
`135
`
`0.50
`
`720
`
`7
`
`85
`
`125
`
`96
`
`89
`
`58
`
`45
`
`34
`
`131
`
`0.50
`
`565
`
`7
`
`68
`
`74
`
`66
`
`54
`
`39
`
`34
`
`30
`
`81
`
`0.50
`
`376
`
`AUC 0-24h
`
`8213
`
`1487
`
`1192
`
`886
`
`[(ng/ml).h]
`
`Form A resulted in blood levels higher than those after administration of surfactant-
`
`20
`
`containing compositions.
`
`Dog Study
`
`Following the above promising results, a relative bioavailability study was performed in
`
`fasted beagle dogs using a dose of 1mglkg body weight. Hard gelatin capsules each
`
`containing lOmg compound X were administered to 8 dogs in a 4-way latin square design;
`
`25
`
`the dogs were fed 6 hours post administration of the capsules, and blood levels of
`
`Par Pharm., Inc.
`Exhibit 1004
`Page 017
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`

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`W097/03654
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`PCT/EP96/03066
`
`-16-
`
`compound X were determined over 48 hours. Similar blood concentration profiles of
`
`compound X were observed for all the dogs, with a terminal halflife of compound X in
`
`blood between 10 and 40 hours. Median peak levels of 140 ng/ml and median AUC levels
`
`of 0-48 hr ca. 1600 ng.hlml were observed.
`
`5 Example 5
`
`A solid dispersion composition is prepared containing the following ingredients (in parts
`
`by weight):
`
`Compound Y
`
`HPMC 3 cps
`
`20
`80
`
`10 The composition (Form E) is prepared by dissolving compound Y and carrier medium in
`
`an ethanoVacetone mixture. The solvents are then evaporated, and the resulting dry
`
`residue milled.
`
`Example 6
`
`A solid dispersion composition is prepared containing the following ingredients (in parts
`
`15
`
`by weight):
`
`Compound Y
`
`HPMC 3 cps
`
`Poloxamer 188
`
`20
`
`70
`
`10
`
`The composition (Form F) is prepared in analogous manner to that in Example 5.
`
`20 Example 7
`
`A solid dispersion composition is prepared containing the following ingredients (in parts
`
`by weight):
`
`Compound Y
`
`HPMC 3 cps
`
`25
`
`Sodium laurylsulfate
`
`20
`75
`
`5
`
`The composition (Form G) is prepared in analogous manner to that in Example 5.
`
`The above compositions Forms E to G may be formed into tab