(12) INTERNATIONAL APPLICATION PUBLISHED
`
`UNDER
`
`THE
`
`PATENT COOPERATION
`
`TREATY
`
`(19) World Intellectual Property Organization
`International Bureau
`
`Date
`(43) International Publication
`11 December 2003 (11.12.2003)
`
`MP
`
`PCT
`
`(51) International Patent Classification7:
`31/397, A61P 9/00
`
`A61K 9/00,
`
`(21) International Application Number: PCT/SE03/00857
`
`(22) International Filing Date: 27 May 2003 (27.05.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`0201658-2
`
`31 May 2002 (31.05.2002) SE
`
`(10) International Publication
`WO 03/101423 A1
`
`Number
`
`GM, HR, HU, ID, IL, IN, IS, IP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NI, NO, NZ, OM, PH, PL,
`
`PT, RO, RU, SC, SD,
`SE, SG, SK, SL, TI, TM, TN, TR, TT, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TI, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, EI, ER, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
`SE, SI, SK, TR), OAPI patent (BE, BI, CE, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (for all designated States except US): AS-
`Declaration under Rule 4.17:
`TRAZENECA AB [SE/SE]; S-151
`85
`Sodertiilje
`(SE).
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17(ii))
`
`for the following designations AE,
`(72) Inventors; and
`AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH,
`(75) Inventors/Applicants (for US only): ABRAHMSEN
`CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, EI,
`ALAMI, Susanna [SE/SE]; AstraZeneca R&D Molndal,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG,
`S-431 83 Molndal (SE). INGHARDT, Tord [SE/SE];
`KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK,
`Molndal, S-431 83 Molndal (SE).
`AstraZeneca R&D
`MN, MW, MX, MZ, NI, NO, NZ, OM,
`PH, PL, PT, RO, RU,
`MAGNUSSON, Anders [SE/SE]; AstraZeneca R &
`SC, SD, SE, SG, SK, SL, TJ, TM, TN, TR,
`TT, TZ,
`UA, UG,
`D Molndal, S-431 83 Molndal (SE). SIGFRIDSSON,
`UZ, VC, VN, YU, ZA, ZM, ZW, ARIPO patent (GH, GM,
`Carl-Gustaf [SE/SE]; AstraZeneca R&D Molndal, S-431
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM,
`ZW),
`83 Molndal (SE). THUNE, Mikael
`[SE/SE]; AstraZeneca
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`R&D Molndal, S-431 83 Molndal (SE).
`
`patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, EI, ER,
`GB, GR, HU, IE, IT, LU, MC, NL, PT, RO, SE, SI, SK, TR),
`OAPI patent (BE, BJ, CE, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG)
`
`Eurasian
`
`(74) Agent: GLOBAL INTELLECTUAL PROPERTY; As
`traZeneca AB, S-151 85 Sodertalje
`(SE).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`Published:
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`GH,
`CZ, DE, DK, DM, DZ, EC, EE, ES,
`EI, GB, GD, GE,
`with international search report
`[Continued on next page]
`
`(54) Title: IMMEDIATE RELEASE PHARMACEUTICAL
`
`FORMULATION
`
`o
`"OH
`v
`\
`
`
`OR
`
`o
`1
`
`(F)n
`
`-R2
`N 7
`NH2
`
`//
`
`H
`N
`
`(I)
`
`m
`Tf
`
`CI
`
`(57) Abstract: According to the present invention there is provided an immediate release pharmaceutical formulation compris­
`ing, as active ingredient, a compound of formula (I), wherein Ri represents C?l-2#191 alkyl substituted by one or more fluoro
`substituents;R2 represents hydrogen, hydroxy, methoxy or ethoxy; andn represents 0, 1 or 2;or a pharmaceutically acceptable salt
`form
`thereof; and a pharmaceutically acceptable
`diluent
`or
`carrier;
`
`that provided the active ingredient is other when
`
`
`than
`in
`the
`salt the formulation does not solely contain:* a
`solution of one
`active
`
`ingredient and water;* a solution of one active ingredient and
`solution of one active ingredient in a mixture of ethanol : PEG 660 12-hydroxy stearate : water 5:5:90;
`such formulations being of use for the treatment of a cardiovascular disorder.
`
`m
`£ dimethylsulphoxide; or* a
`
`of a
`
`MYLAN - EXHIBIT 1032
`
`

`

`WO 03/101423 A1
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`For two-letter codes and other abbreviations, refer to the "Guid­
`ance Notes on Codes and Abbreviations" appearing at the begin­
`ning of each regular issue of the PCT Gazette.
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`WO 03/101423
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`PCT/SE03/00857
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`1
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`5
`
`IMMEDIATE RELEASE PHARMACEUTICAL FORMULATION
`This invention relates to a novel immediate release pharmaceutical formulation that
`provides for the delivery of particular pharmaceuticals, to the manufacture of such a
`formulation, and to the use of such a formulation in the treatment or prevention of
`thrombosis.
`It is often desirable to formulate pharmaceutically active compounds for immediate
`release following oral and/or parenteral administration with a view to providing a sufficient
`concentration of drug in plasma within the time-frame required to give rise to a desired
`therapeutic response.
`Immediate release may be particularly desirable in cases where, for example, a rapid
`therapeutic response is required (for example in the treatment of acute problems), or, in the
`case of parenteral administration, when peroral delivery to the gastrointestinal tract is
`incapable of providing sufficient systemic uptake within the required time-frame.
`In the case of the treatment or prophylaxis of thrombosis, immediate release
`formulations may be necessary to ensure that a sufficient amount of drug is provided in
`plasma within a relatively short period of time to enable quick onset of action. Immediate
`release formulations are also typically simpler to develop than modified release
`formulations, and may also provide more flexibility in relation to the variation of doses that
`are to be administered to patients. Immediate release formulations are superior when
`20 multiple doses are not required and where it is not necessary to keep the plasma
`
`10
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`15
`
`concentration at a constant level for an extended time.
`International Patent Application No. PCT/SEO1/02657 (WO 02/44145, earliest
`priority date 01 December 2000, filed 30 November 2001, published 06 June 2002)
`discloses a number of compounds that are, or are metabolised to compounds which are,
`competitive inhibitors of trypsin-like proteases, such as thrombin. The following three
`compounds are amongst those that are specifically disclosed:
`(a)Ph(3-Cl)(5-0CHF2)-(/?)CH(0H)C(0)-(5)Aze-Pab(0Me):
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`2
`
`O
`
`l
`
`HO
`
`r
`
`CI
`
` o
`
`OCHF2
`
`PH3
`/
`N^0
`
`NH2
`
`which compound is referred to hereinafter as Compound A;
`(b)Ph(3-Cl)(5-0CHF2)-(i?)CH(0H)C(0)-(5)Aze-Pab(2,6-diF)(0Me):
`PH3
`/
`-O
`N
`'I
`
`O
`
`HO
`
`F.
`
`Ulr
`" r " ' ^ N n h2
`o
`
`I
`
`CI
`
`OCHF2
`
`F
`
`5 which compound is referred to hereinafter as Compound B; and
`(c) Ph(3-Cl)(5-0CH2CH2F)-(i?)CH(0H)C(0)-(5)Aze-Pab(0Me):
`
`O
`
`N
`
`UL
`l
`
`HO
`
`r
`
`PH3
`/
`N"0
`
`NH2
`
` o
`
`CI
`
`OCH2CH2F
`
`which compound is referred to hereinafter as Compound C.
`The methoxyamidine Compounds A, B and C are metabolised following oral and/or
`parenteral administration to the corresponding free amidine compounds, which latter
`compounds have been found to be potent inhibitors of thrombin. Thus:
`
`10
`
`Compound A is metabolized to Ph(3-Cl)(5-0CHF2)-(/?)CH(0H)C(0)-(lS,)Aze-Pab
`(which compound is referred to hereinafter as Compound D) via a prodrug intermediate
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`
`Ph(3-Cl)(5-0CHF2)-(i?)CH(0H)C(0)-(5,)Aze-Pab(0H) (which compound is referred to
`hereinafter as Compound G);
`Compound B is metabolized to Ph(3-Cl)(5-0CHF2)-(^)CH(0H)C(0)-(5)Aze-
`Pab(2,6-diF) (which compound is referred to hereinafter as Compound E) via a prodrug
`intermediate Ph(3-Cl)(5-0CHF2)-(/?)CH(0H)C(0)-(5)Aze-Pab(2,6-diF)(0H) (which
`compound is referred to hereinafter as Compound H); and,
`Compound C is metabolized to Ph(3-Cl)(5-0CH2CH2F)-(2?)CH(0H)C(0)-(5)Aze-
`Pab (which compound is referred to hereinafter as Compound F) via a prodrug intermediate
`Ph(3-Cl)(5-0CH2CH2F)-(/?)CH(0H)C(0)-(5,)Aze-Pab(0H) (which compound is referred
`to hereinafter as Compound J).
`Processes for the synthesis of Compounds A, B, C, D, E, F, G and J are described in
`Examples 12, 40, 22, 3, 39, 21, 2 and 31 (respectively) of international patent application
`No. PCT/SEO1/02657. An immediate release formulation of these compounds, or their
`metabolites has yet to be described in the literature. We have found that the compounds of
`formula (I) and their salts can be formulated as immediate release pharmaceutical
`formulations which are easy to administer, for example by oral or parenteral
`administration.
`According to a first aspect of the invention, there is provided an immediate release
`pharmaceutical formulation comprising, as active ingredient, a compound of formula (I):
`O
`(F)n
`H
`N % J
`
`—R2
`N
`/
`NH2
`
`(I)
`
`5
`
`10
`
`15
`
`o
`
`20
`
`Ci
`
`wherein
`R1 represents C1.2 alkyl substituted by one or more fluoro substituents;
`R represents hydrogen, hydroxy, methoxy or ethoxy; and
`n represents 0, 1 or 2;
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`
`or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or
`carrier;
`provided that the formulation does not solely contain:
`• a solution of one active ingredient and water;
`• a solution of one active ingredient and dimethylsulphoxide; or,
`• a solution of one active ingredient in a mixture of ethanol: PEG 660 12-hydroxy
`stearate ; water 5:5:90;
`which formulations are referred to hereinafter as "the formulations of the invention".
`PEG 660 12-hydroxy stearate is a non-ionic surfactant and is better known as
`SolutolK™
`According to a second aspect of the present invention there is provided Compound H.
`Ph(3-Cl)(5-0CHF2)-(i?)CH(0H)C(0)-GS)Aze-Pab(2,6-diF)(0H) which can be prepared by
`methods similar to those described below for the preparation of Compounds G and J.
`The compounds of formula (I), or a pharmaceutically acceptable salt thereof, may
`be in the form of a solvate, a hydrate, a mixed solvate/hydrate or, preferably, an ansolvate,
`such as an anhydrate. Solvates may be of one or more organic solvents, such as lower (for
`example CM) alkyl alcohols (for example methanol, ethanol or zso-propanol), ketones
`(such as acetone), esters (such as ethyl acetate) or mixtures thereof.
`In one particular aspect of the invention R1 is CHF2 or CH2CH2F.
`The variable n is preferably 0 or 2.
`More preferred compounds of formula (I) include those in which n represents 0, or
`those in which n represents 2, so providing two fluoro atoms located at the 2- and 6-
`positions (that is the two orf/io-positions relative to the point of attachment of the benzene
`ring to the -NH-CH2- group).
`The compound of formula (I) is especially Compound A, Compound B or Compound
`
`Preferred salts of the compounds of formula (I) are acid addition salts. Acid
`addition salts include inorganic acid addition salts, such as those of sulphuric acid, nitric
`acid, phosphoric acid and hydrohalic acids, such as hydrobromic acid and hydrochloric
`acid. More preferred acid addition salts include those of organic acids, such as those of
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`dimethylphosphoric acid; saccharinic acid; cyclohexylsulfamic acid; those of carboxylic
`acids (such as maleic acid, fumaric acid, aspartic acid, succinic acid, malonic acid, acetic
`acid, benzoic acid, terephthalic acid, hippuric acid, l-hydroxy-2-naphthoic acid, pamoic
`acid, hydroxybenzoic acid and the like); those of hydroxy acids (such as salicylic acid,
`tartaric acid, citric acid, malic acid (including L-(-)-malic acid and, D,L-malic acid),
`gluconic acid (including D-gluconic acid), glycolic acid, ascorbic acid, lactic acid and the
`like); those of amino acids (such as glutamic acid (including D-glutamic, L-glutamic, and
`D,L-gIutamic, acids), arginine (including L-arginine), lysine (including L-lysine and L-
`lysine hydrochloride), glycine and the like); and, particularly, those of sulfonic acids, (such
`as 1,2-ethanedisulfonic acid, camphorsulfonic acids (including lS-(+)-10-camphorsulfonic
`acid and (+/-)-camphorsulfonic acids), ethanesulfonic acid, a propanesulfonic acid
`(including n-propanesulfonic acid), a butanesulfonic acid, a pentanesulfonic acid, a
`toluenesulfonic acid, methanesulfonic acid, p-xylenesulfonic acid, 2-mesitylenesulfonic
`acid, naphthalenesulfonic acids (including 1,5-naphthaIenesulfonic acid and
`naphthalenesulfonic acid), benzenesulfonic acid, hydroxybenzenesulfonic acids, 2-
`hydroxyethanesulfonic acid, 3-hydroxyethanesulfonic acid and the like).
`Particularly preferred salts include those of Cj-e (for example C1-4) alkanesulfonic
`acids, such as ethanesulfonic acid (esylate) and propanesulfonic acid (for example n-
`propanesulfonic acid) and optionally substituted (for example with one or more C1.2 alkyl
`groups) arylsulfonic acids, such as benzenesulfonic acid (besylate) and
`naphthalenedisulfonic acid.
`Suitable stoichiometric ratios of acid to free base are in the range 0.25:1.5 to 3.0:1,
`such as 0.45:1.25 to 1.25:1, including 0.50:1 to 1:1.
`According to a further aspect of the invention there is provided formulation
`comprising a compound of formula (I) in substantially crystalline form.
`Although we have found that it is possible to produce compounds of the invention
`in forms which are greater than 80% crystalline, by "substantially crystalline" we include
`greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g.
`greater than any of 50, 60,70, 80 or 90%) crystalline.
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`
`According to a further aspect of the invention there is also provided a
`compound of the invention in partially crystalline form. By "partially crystalline"
`we include 5% or between 5% and 20% crystalline.
`The degree (%) of crystallinity may be determined by the skilled person using X-ray
`powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman
`spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be
`used.
`
`Preferred compounds of formula (I) that may be prepared in crystalline form
`include salts of Cj.g (for example C2-6, such as C2-4) alkanesulfonic acids, such as
`ethanesulfonic acid, propanesulfonic acid (for example n-propanesufonic acid) and
`optionally substituted arylsulfonic acids, such as benzenesulfonic acid and
`naphthalenedisulfonic acid.
`The term "immediate release" pharmaceutical formulation includes any formulation
`in which the rate of release of drug from the formulation and/or the absorption of drug, is
`neither appreciably, nor intentionally, retarded by galenic manipulations. In the present
`case, immediate release may be provided for by way of an appropriate pharmaceutically
`acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable
`extent, the rate of drug release and/or absorption. Thus, the term excludes formulations
`which are adapted to provide for "modified", "controlled", "sustained", "prolonged",
`"extended" or "delayed" release of drug.
`In this context, the term "release" includes the provision (or presentation) of drug
`from the formulation to the gastrointestinal tract, to body tissues and/or into systemic
`circulation. For gastrointestinal tract release, the release is under pH conditions such as pH
`= 1 to 3, especially at, or about, pH = 1. In one aspect of the invention a formulation as
`described herein with a compound of formula (I), or an acid addition salt thereof, in
`crystalline form releases drug under a range of pH conditions. In another aspect of the
`invention a formulation as described herein with a compound of formula (I), or an acid
`addition salt thereof, releases drug under pH conditions such as pH = 1 to 3, especially at,
`or about, pH = 1. Thus, formulations of the invention may release at least 70% (preferably
`80%) of active ingredient within 4 hours, such as within 3 hours, preferably 2 hours, more
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`preferably within 1.5 hours, and especially within an hour (such as within 30 minutes), of
`administration, whether this be oral or parenteral.
`The formulations of the invention may be formulated in accordance with a variety of
`known techniques, for example as described by M. E. Aulton in "Pharmaceutics: The
`Science of Dosage Form Design" (1988) (Churchill Livingstone), the relevant disclosures in
`which document are hereby incorporated by reference.
`Formulations of the invention may be, or may be adapted in accordance with
`standard techniques to be, suitable for peroral administration, for example in the form of an
`immediate release tablet, an immediate release capsule or as a liquid dosage form,
`comprising active ingredient. These formulation types are well known to the skilled person
`and may be prepared in accordance with techniques known in the art.
`Suitable diluents/carriers (which may also be termed "fillers") for use in peroral
`formulations of the invention, for example those in the form of immediate release tablets,
`include monobasic calcium phosphate, dibasic calcium phosphate (including dibasic
`calcium phosphate dihydrate and dibasic calcium phosphate anhydrate), tribasic calcium
`phosphate, lactose, microcrystalline cellulose, silicified microcrystalline cellulose,
`mannitol, sorbitol, starch (such as maize, potato or rice), glucose, calcium lactate, calcium
`carbonate and the like. Preferred diluents/carriers include dibasic calcium phosphate and
`microcrystalline cellulose, which may be used alone or in combination with another
`diluent/carrier such as mannitol.
`A formulation of the invention in the form of an immediate release tablet may
`comprise one or more excipients to improve the physical and/or chemical properties of the
`final composition, and/or to facilitate the process of manufacture. Such excipients are
`conventional in the formulation of immediate release formulations for peroral drug
`delivery, and include one or more of the following: one or more lubricants (such as
`magnesium stearate, stearic acid, calcium stearate, stearyl alcohol or, preferably, sodium
`stearyl fumarate); a glidant (such as talc or a colloidal silica); one or more binders (such as
`polyvinylpyrrolidone, microcrystalline cellulose, a polyethylene glycol (PEG), a
`polyethylene oxide, a hydroxypropylmethylcellulose (HPMC) of a low molecular weight, a
`30 methylcellulose (MC) of a low molecular weight, a hydroxypropylcellulose (HPC) of a low
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`molecular weight, a hydroxyethylcellulose (HEC) of a low molecular weight, a starch (such
`as maize, potato or rice) or a sodium carboxymethyl cellulose of a low molecular weight;
`(preferred binders are polyvinylpyrrolidone or a HPMC of a low molecular weight); one or
`more pH controlling agents (such as an organic acid (for example citric acid) or an alkali
`5 metal (for example sodium) salt thereof, an oxide of magnesium, an alkali or alkaline earth
`metal (for example sodium, calcium or potassium) sulphate, metabisulphate, propionate or
`sorbate); one or more disintegrant (for example sodium starch glycollate, a crosslinked
`polyvinylpyrrolidone, a crosslinked sodium carboxymethyl cellulose, a starch (such as
`maize, potato or rice) or an alginate); a colourant, a flavouring, a tonicity-modifying agent,
`a coating agent or a preservative.
`It will be appreciated that some of the above mentioned excipients which may be
`present in a final immediate release oral (for example tablet) formulation of the invention
`may have more than one of the above-stated functions.
`In a farther aspect of the invention a liquid formulation of the invention is adapted
`to be suitable for oral administration.
`Suitable liquid formulations that are to be administered orally include those in which
`a compound of formula (I) especially Compound A, Compound B or Compound C, or a
`pharmaceutically acceptable salt thereof is presented together with an aqueous carrier, such as
`water. It will be noted however, that certain specific formulations are not claimed (see
`particular aspects and the claims).
`A formulation of the present invention comprising an aqueous carrier may further
`comprise one or more excipients, such as an antimicrobial preservative; a tonicity modifier
`(for example sodium chloride, mannitol or glucose); a pH adjusting agent (for example a
`common inorganic acid or base, including hydrochloric acid or sodium hydroxide); a pH
`controlling agents (that is, a buffer; for example tartaric acid, acetic acid or citric acid); a
`surfactant (for example Sodiun dodecyl sulphate (SDS) or Solutol™); a solubiliser which
`serves to help solubilise the active ingredient (for example ethanol, a polyethylene glycol or
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`
`hydroxypropyl-P-cyclodextrin or polyvinyl chloride (PVP)); or an antioxidant.
`
`Liquid oral formulations may be in the form of suspensions of active
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`
`ingredient in association with an aqueous solvent or, more preferably aqueous
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`ii.
`
`iii.
`
`solutions (that is, solutions of active compound including water as a solvent). In
`this context, the term "aqueous solution" includes formulations in which at least
`99% of active ingredient is in solution at above 50C and atmospheric pressure, and
`the term "suspension" means that more than 1 % of active ingredient is not in
`solution under such conditions. Typical dispersion agents for suspensions are
`hydroxypropyl methylcellulose, AOT (dioctylsulfosuccinate), PVP and SDS.
`Other alternatives may be possible.
`In another aspect the present invention provides a liquid oral formulation comprising
`a compound of formula (I), or a pharmaceutically acceptable salt thereof, water and at least
`one additional agent. The additional agents include :
`polyethylene glycol (PEG) and optionally also ethanol and/or tartaric acid and/or
`i.
`citric acid and/or hydrochloric acid; or
`sodium chloride (which will be dissolved in the formulation), and optionally also
`ethanol; or
`hydrochloric acid and/or sodium hydroxide to bring the pH to a suitable value
`(preferably in the range 3 - 8 for a compound of formula (I) wherein R2 is methoxy or
`ethoxy, such as Compound A, B or C); or
`iv. DMA (dimethyl acetamide) and optionally also a medium chain triglyceride (such as
`miglyol); or
`a P-cyclodextrin (such as hydroxypropyl-p-cyclodextrin);
`a tonicity modifier such as sodium chloride and/or mannitol.
`In a further aspect the present invention provides an oral solution comprising a
`compound of formula (I), or a pharmaceutically acceptable salt thereof, (preferably
`Compound A, B or C) water and at least one additional agents as recited in (i) to (vi) above.
`In another aspect the invention provides an aqueous formulation of a compound of
`formula (I) (such as Compound A, B or C) comprising a solubilising agent such as a
`polyethylene glycol, P-cyclodextrin (such as hydroxypropyl-(3-cyclodextrin), sorbitol or
`ethanol.
`
`v.
`vi.
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`In a further aspect the present invention provides an oral solution formulation
`comprising a compound of formula (I) and ethanol. This formulation can further comprise a
`medium chain triglyceride (such as miglyol).
`In a still further aspect the present invention provides an oral solution formulation
`comprising a compound of formula (I) and DMA. This formulation can further comprise a
`medium chain triglyceride (such as miglyol).
`In another aspect the compound of formula (I) is crystalline (especially a salt of
`Compound A; preferably a Q-g (for example C2-6, such as C2-4) alkanesulfonic acid salt,
`such as ethanesulfonic acid, propanesulfonic acid (for example n-propanesufonic acid) or
`an optionally substituted arylsulfonic acid salt, such as benzenesulfonic acid or
`naphthalenedisulfonic acid salt).
`A particular liquid immediate release oral pharmaceutical formulation as claimed in
`claim 1 is provided wherein the active ingredient is:
`Ph(3-Cl)(5-0CHF2)-(i?)CH(0H)C(0)-(>S)Aze-Pab(0Me),
`Ph(3-Cl)(5-0CHF2)-(/?)CH(0H)C(0)-(5)Aze-Pab(2)6-diF)(0Me),
`Ph(3-Cl)(5-0CH2CH2F)-(/?)CH(0H)C(0)-(5)Aze-Pab(0Me),
`or a pharmaceutically acceptable salt thereof.
`A further particular liquid immediate release oral pharmaceutical formulation as
`claimed in claim 1 is provided wherein the active ingredient is:
`Ph(3-Cl)(5-0CHF2)-(/?)CH(0H)C(0)-(5)Aze-Pab(0Me) or a C].6 alkanesulfonic acid or an
`optionally substituted arylsulfonic acid salt thereof.
`A yet further particular liquid immediate release oral pharmaceutical formulation as
`claimed in claim 1 is provided wherein the active ingredient is:
`Ph(3-Cl)(5-0CHF2)-(i?)CH(0H)C(0)-GS)Aze-Pab(2,6-diF)(0Me) or an optionally
`substituted arylsulfonic acid salt thereof (such as the naphthalene- 1,5-disulphonic acid
`salt).
`
`It will be noted however, that certain specific formulations are not claimed (see
`particular aspects and the claims).
`In a further aspect of the invention a formulation of the invention is adapted to be
`suitable for parenteral administration. The term "parenteral" includes any mode of
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`administration that does not comprise peroral administration to the gastrointestinal tract
`and includes administration subcutaneously, intravenously, intraarterially, transdermally,
`intranasally, intrabuccally, intracutaneously, intramuscularly, intralipomateously,
`intraperitoneally, rectally, sublingually, topically, by inhalation, or by any other parenteral
`route.
`
`Suitable formulations of the invention that are to be administered parenterally include
`those in which a compound of formula (I) or a pharmaceutically acceptable salt thereof is
`presented together with an aqueous carrier, such as water.
`A formulation of the present invention comprising an aqueous carrier may further
`comprise one or more excipients, such as an antimicrobial preservative; a tonicity modifier
`(for example sodium chloride, mannitol or glucose); a pH adjusting agent (for example a
`common inorganic acid or base, including hydrochloric acid or sodium hydroxide); a pH
`controlling agents (that is, a buffer; for example tartaric acid, acetic acid or citric acid); a
`surfactant (for example sodium dodecyl sulphate (SDS) or Solutol™); a solubiliser which
`serves to help solubilise the active ingredient (for example ethanol, a polyethylene glycol or
`hydroxypropyl-(3-cyclodextrin or polyvinyl chloride (PVP)); or an antioxidant.
`Parenteral formulations may be in the form of suspensions of active ingredient in
`association with an aqueous solvent or, more preferably aqueous solutions (that is, solutions
`of active compound including water as a solvent). In this context, the term "aqueous
`solution" includes formulations in which at least 99% of active ingredient is in solution at
`above 50C and atmospheric pressure, and the term "suspension" means that more than 1% of
`active ingredient is not in solution under such conditions. Typical dispersion agents for
`suspensions are hydroxypropyl methylcellulose, AOT, PVP and SDS, but other alternatives
`are possible.
`The number of excipients employed in the peroral and parenteral formulations of the
`invention depends upon many factors, such as the nature and amount of active ingredient
`present, and the amount of diluent/carrier (aqueous solvent or otherwise) that is included.
`In another aspect the present invention provides a parenteral formulation comprising a
`compound of formula (I), or a pharmaceutically acceptable salt thereof, water and at least one
`additional agents. The additional agents include:
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`iv.
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`v.
`vi.
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`polyethylene glycol (PEG) and optionally also ethanol and/or tartaric acid and/or
`hydrochloric acid; or
`sodium chloride (which will be dissolved in the formulation), and optionally also
`ethanol; or
`hydrochloric acid and/or sodium hydroxide to bring the pH to a suitable value
`(preferably in the range 3-8 for a compound of formula (I) wherein R2 is hydrogen,
`such as Compound D, E or F; or preferably in the range 3.5-8 for a compound of
`formula (I) wherein R2 is methoxy or ethoxy, such as Compound A, B or C); or
`DMA (dimethyl acetamide) and optionally also a medium chain triglyceride (such as
`miglyol); or
`a p-cyclodextrin (such as hydroxypropyl-(3-cyclodextrin);
`a tonicity modifier such as sodium chloride and/or mannitol.
`In a further aspect the present invention provides an injectable solution comprising a
`compound of formula (I), or a pharmaceutically acceptable salt thereof, (preferably
`Compound D, E or F) water and at least one additional agents as recited in (i) to (vi) above.
`In another aspect the invention provides an aqueous formulation of a compound of
`formula (I) (such as Compound D, E or F) comprising a solubilising agent such as a
`polyethylene glycol, P-cyclodextrin (such as hydroxypropyl-j3-cyclodextrm), sorbitol or
`ethanol.
`In a further aspect the present invention provides a parenteral formulation comprising
`a compound of formula (I) and ethanol. This formulation can further comprise a medium
`chain triglyceride (such as miglyol).
`In a still further aspect the present invention provides a parenteral formulation
`comprising a compound of formula (I) and DMA. This formulation can further comprise a
`medium chain triglyceride (such as miglyol).
`In another aspect the compound of formula (I) is crystalline (especially a salt of
`Compound A; preferably a Q.e (for example C2-6, such as C2-4) alkanesulfonic acid salt,
`such as ethanesulfonic acid, propanesulfonic acid (for example n-propanesufonic acid) or
`an optionally substituted arylsulfonic acid salt, such as benzenesulfonic acid salt).
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`In yet another aspect the formulation of the present invention is in a solid dosage form
`wherein R2 is hydroxy, methoxy or ethoxy (preferably methoxy) (the compound of formula
`(I) is especially Compound A, Compound B or Compound C).
`In yet another aspect the present invention provides a parenteral formulation
`(especially a water-based, injectable solution) comprising a compound of formula (I) in free
`base form.
`In a further aspect the present invention provides a parenteral formulation comprising
`a compound of formula (I) in free base form wherein R2 is hydrogen.
`In a still further aspect the present invention provides a solid formulation comprising
`10 microcrystalline cellulose and polyvinyl pyrrolidone (PVP); or comprising microcrystalline
`cellulose and sodium starch glycollate.
`Formulations of the invention, such as parenteral formulations, comprising salts
`may be prepared by addition of diluent/carrier to the appropriate pre-prepared salt.
`Compositions including active ingredient may also be provided in solid form
`suitable for use in the preparation of a formulation of the invention (for example a solution,
`such as an aqueous solution, for example for parenteral adminstration) ex tempore. Such
`compositions may be in the form of a solid comprising active ingredient, optionally in the
`presence of one or more further excipients as hereinbefore defined and, optionally, up to
`10% (w/w) of diluent and/or carrier as hereinbefore defined, which compositions are
`hereinafter referred to as "the solid compositions of the invention".
`Solid compositions of the invention may be made by removal of diluent/carrier (for
`example solvent) from a formulation of the invention, or a concentrated formulation of the
`invention, which may for example be in the form of a solution, such as an aqueous
`solution.
`In another aspect the present invention provides an orally administerable,
`immediate release formulation comprising a compound of formula (I), or a salt thereof, a
`carrier (such as microcrystalline cellulose), a disintegrant (such as sodium starch
`glycollate), a binder (such as polyvinyl pyrrolidone) and a lubricant (such as sodium stearyl
`fumarate). Such a formulation may also comprise an additional carrier (or filler) such as
`30 mannitol.
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`Formulations of the invention that are in the form of immediate release tablets may
`be prepared by bringing active ingredient into association with diluent/carrier using
`standard techniques, and using standard equipment, known to the skilled person, including
`wet or dry granulation, direct compression/compaction, drying, milling, mixing, tableting
`and coa