NZ612420B2 - S1p receptor modulator modified release formulations - Google Patents

Abstract

Disclosed is a solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and siponimod (BAF312 / 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid) or a pharmacologically acceptable salt (particularly the hemifumarate salt), solvate or hydrate thereof, wherein siponimod is in a mixture of materials which is free of basic compounds, with the exclusion of basic forms of siponimod itself. Also disclosed is a solid phase pharmaceutical composition such as a tablet comprising one or more pharmaceutically acceptable excipients and siponimod , wherein siponimod has a crystallinity of 80% or more and wherein the siponimod is in a mixture of materials which is free of basic compounds, with the exclusion of basic forms of siponimod itself. the hemifumarate salt), solvate or hydrate thereof, wherein siponimod is in a mixture of materials which is free of basic compounds, with the exclusion of basic forms of siponimod itself. Also disclosed is a solid phase pharmaceutical composition such as a tablet comprising one or more pharmaceutically acceptable excipients and siponimod , wherein siponimod has a crystallinity of 80% or more and wherein the siponimod is in a mixture of materials which is free of basic compounds, with the exclusion of basic forms of siponimod itself.

Description

S1P RECEPTOR MODULATOR MODIFIED RELEASE FORMULATIONS Field of the Invention The present invention relates to formulations of immunosuppressant compounds, and particularly to formulations of 81 P or modulators. More particularly the invention relates to formulations of 1-{4—[1-(4-cyclohexyltrifluoromethyl—benzyloxyimino)-ethyl]—2— ethyl-benzyl}—azetidine-3—carboxylic acid, pharmaceutically acceptable salts, and related compounds.

Background to the Invention 81 P receptors belong to a family of closely related, lipid activated G- protein coupled receptors. S1P1, 81 P3, 81P2, 81P4, and SiP5 (also respectively termed EDG-1, EDG-3, EDG-5, EDG-6, and EDG-8) are identified as receptors specific for sphingosine-t-phosphate (81 P). n 81 P receptors are associated with diseases mediated by lymphocyte interactions, for e, in transplantation rejection, autoimmune disease, inflammatory diseases, infectious diseases and .

W02004/103306 discloses immunosuppressant compounds that are useful in the treatment of diseases associated with 81 P receptor mediated signal transduction. The immunosuppressant compounds disclosed in W02004/103306 affect the pathology and/or symptomology of these diseases by altering the activity of 81 P receptors. In particular, /103306 and US 2009/0036423 disclose 1—{4-[1-(4—cyclohexyltrifluoromethyl— benzyloxyimino)-ethyl]-2—ethyl~benzyl}-azetidine-3—carboxylic acid: N CF3 and methods for making this compound. The nds are disclosed as useful in the treatment and/or prevention of es and disorders ed by lymphocyte interactions, for example autoimmune diseases, e.g. rheumatoid tis, systemic lupus erythematosus, Hashimoto’s thyroiditis and muitiple sclerosis, amongst many others. W020041103306 and US 2009/0036423 are incorporated herein by reference for ail purposes, including by way of non—limiting e paragraphs {0041140054}, inclusive, of US 2009/0036423 and each exampie thereof.

WOZOi 1 U discloses use of 81 P receptor agonists, for example 1-{4-[1—(4—cyclohexyl— 3-trifiuoromethyi—benzyloxyimino)-ethyi]—2—ethyl—benzyi}-azetidine—B—carboxylic acid, in the treatment of peripheral neurapathies, such as Guiiiain-Barre syndrome (GBS), chronic inflammatory demyelinating poiyradicuioneuropathy (CIDP), muitifocai motor athy with conduction biock (MMN), and paraproteinaemic demyeiinating peripheral athy (PDN).

W02007/021666 discloses a concentrate for diiution sing a 81 P receptor agonist, propylene glycol and optionally glycerin, which trate is described as being stable for extended periods of time. One compound mentioned as an SiP receptor agonist is 1-{4—[1- (4‘cyciohexyi—3—trifluoromethyi—benzyIoxyimino)—ethyi]-2—ethyl~benzyi}-azetidine~3-carboxylic acid. The dilution disclosed in W02007/021666 is provided in a liquid form and is therefore particulariy suitabie for patients who struggle to swallow solid tions.

W02009IO48993 discloses compositions comprising S‘iP'receptor tors, such as 2— substituted Z—amino-propane-i ,3-diol or 2-amino-propanol derivatives, which are suitable for use as an orai dosage form. The composition is disclosed to se the active ingredient and one or more of various specified excipients. Example it) mentions giyceryi behenate as a asible ent, seemingiy because of degradation of the active (FTY720). One 81 P modulator mentioned is 1—{4—[1-(4~cyciohexyl—3~trifiuoromethyi-benzyioxyimino)—ethyi]«2~ ethyl-benzyi}azetidine-3—carboxyiic acid.

W02010/072708 discloses a dosage regimen of an 81 P receptor modulator for the treatment of patients suffering from an autoimmune disease, for example multiple scierosis.

The dosage regimen comprises administering a tower dosage of an SiP receptor moduiator during the initial days of treatment compared to the standard daily dosage. The dosage is then increased stepwise up to the standard daily dosage of the 81 P receptor modulator.

One 81 P moduiator mentioned is 1«{4«[1~(4~cyclohexyl~3-trifiuoromethyl-benzyioxyiminc)- ethyl}ethyl-benzyl}azetidine-3—carboxyiic acid.

Summag of the invention The present invention is ated at least in part on a finding that, in relation to active ceutical ingredients described later in this specification, ceutics! compositions having particular excipients are associated with reduced degradation of the active pharmaceutical ingredient as compared to atternative compositions of the same active pharmaceutical ingredient.

The invention is also predicated at least in part by a finding that provision of the active ceutical ingredient as particles of relatively large size can improve stability Whiist maintaining an adequately homogeneous content uniformity.

The compounds to which the appiication relates are compounds as discioseci in WC 04/103306 and US 2009;0036423, in particuiar compounds of formula A1 or A2: A—2 ‘71” “>53 R2 N A—Z Y w o\N2\ A1 A2 wherein A is COORS, OPO(OR5)2, PO(OR5)2, SOZORS, P0R50R5 or 1H~tetrazoi-5—yi, R5 being H or an ester-forming group, eg. Citsalkyl, and in one impiementation of the invention being H; W is a bond, C1_3alkyiene or 02.3aikeriylene; Y is yl or ngheteroaryi, optionaiiy tuted by 1 to 3 radicals seiected from halogen, N02. 01.6alkyl, Cwaikoxy; halo-substituted Cmalkyl and halo—substituted C1_aaikoxy; Z is chosen from: *\N/\/\/*; *\f?}/\/\* , *\[?1/\* 1 *\'?1/\/ 1 \ g", R6 R6 R6 R6 9: a: * 94 *—-e*-\l ,, * , mm Ni , a: * F126 *\ s- \N k ; N ; N . \N I kl ‘ N I 3 R6 F */ 4.- * R6 \ T O * $6 N N i .140 NW“ upl ;« R6 N\/\* * W HO *J * 1 * A/ * ’*/\l}3/\‘/ * *_ \ \N , \N , \N ,and at l l $6 R5 l R6 Re Re * wherein the asterisks of Z te the point of attachment between -C(R3)(R4)- and A of Formula la or lb, respectively; R5 is chosen from hydrogen and Cmalkyl; and J1 and J2 are independently methylene or a heteroatom chosen from 8, O and NR5; wherein R5 is chosen from hydrogen and Cmalkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, l; or R; can be attached to a carbon atom of Y to form a 5—? member ring; R1 is Cmoaryl or 03-9heteroaryl, optionally tuted by Cmalkyl, Cs_1oaryl, Ca.1oarleMalkyl, Casheteroaryl. C3.gheteroarleMalkyl, Cg_goyoloalkyl, CmcycloalkleMalkyl, Csugheterocycloalkyl or 03.3heierocycioalkleMaikyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R1 may be substituted by 1 to 5 groups selected from halogen, C1. aalkyl, Cmalkoxy and halo substituted5alkyl or -Cmalkoxy; R2 is H, (31.5alkyl, halo tuted (31.5elkyl, Czaalkenyl or Czealkynyl; and each of R3 or R4, ndently, is H, halogen, OH, Cmalkyl, Cmalkoxy or halo substituted Cwalkyl or C1,ealkoxy; W0 2012f093161 'l or a pharmacologically acceptable salt, solvate or hydrate thereof. in the above formula, the designation “(315” means "having 1, 2, 3, 4, 5 or 6 carbon atoms” and the designation "Cm” means "having 3, 4, 5, 6, 7 or 8 carbon atoms”. The designation "01.4” means “having 1, 2, 3 or 4 carbon atoms”. The designation “03-9" means “having 3, 4, , 6, 7, 8 or 9 carbon atoms”.

The invention particularly, but not exclusively, involves compounds of formula A1 or A2 in which R5 is H, eg. moiety A is ~COOH, in its acid form (not therefore as a salt thereof).

An exemplary compound of formula A1 or A2 is 1~{4—{1»(4«cyciohexylirifluoromethyl» benzyloxyimino)—ethy|}—2—ethyl-benzyl}~azetidine—B—carboxylic acid and its pharmaceutically acceptable salts, eg. its hemifumarate salt. in one aspect, the invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient ("APl") ed from the compounds of Formulae A1 and A2, and one or more pharmaceutically acceptable excipients, wherein the APl is not exposed to a basic compound. in another aspect, the invention es a pharmaceutical composition comprising an active ceutical ingredient ) selected from the compounds of Formulae A1 and A2, wherein the AP! is in the form of particles having an X90 diameter of at least 8pm and optionally of at least 10pm.

The invention also provides a pharmaceutical composition comprising an active pharmaceutical ingredient (“APl”) selected from the compounds of Formulae A1 and A2, n the AP! is in the form of les having a llinity of 80% or more.

Further included in the invention are pharmaceutical compositions comprising an active pharmaceutical ingredient (“API”) selected from the nds of Formulae A1 and A2, wherein the APl is in the form of les having an X90 er of at least 8pm and optionally of at least 10pm and a crystallinity of 80% or more.

The invention includes a pharmaceutical composition comprising an active pharmaceutical ingredient (“APl”) selected from the compounds of Formulae A1 and A2, and one or more ceutically acceptable excipients, wherein the APi is in the form of particles which have an X90 diameter of at least 8pm and optionally of at least 10pm and which are not exposed to a basic compound. in an embodiment, the composition is free of basic compounds.

The invention includes pharmaceutical compositions comprising an active pharmaceutical ingredient (“APl”) selected from the compounds of ae A1 and A2, and one or more pharmaceutically acceptabie ents, wherein the APl is in the form of particles which have a crystallinity of 80% or more and which are not exposed to a basic compound.

Additionally to be mentioned as provided by the invention are pharmaceutical compositions comprising an active pharmaceutical ingredient ) selected from the nds of Formuiae A1 and A2, and one or more ceutically acceptable excipients, wherein the API is in the form of particles which have have an X90 diameter of at least 8pm and optionally of at ieast 10pm and a crystallinity of 80% or more and which are not exposed to a basic compound.

The composition is in particuiar a solid phase composition, for example a tablet or capsule, particularly a tablet. The composition may be coated with a moisture barrier and an ary composition is a tablet coated with a moisture barrier.

The pharmaceutical composition may therefore se, or consist of, at least one APl and one or more non—basic excipients. The one or more non-basic excipients may be selected from binders, disintegrants, giidants, lubricants, fillers, diluents, and/or ts. The tablets may comprise one or more tablet ants wherein the lubricants in the tablets are selected exclusively from stearic acid, hydrogenated vegetabie oii, mineral oil, polyethylene glycol 4000-6000, l palmitostearate and glyceryi behenate. in one embodiment, the pharmaceutical composition comprises a non-basic sustained release agent, for example a sic hydrogei former, eg. a hypromeilose (hydroxypropyimethyl cellulose).

A particular embodiment resides in a tablet comprising a ssed mixture which consists of 1 -{4-[1-(4-cyciohexyl-S»trifiuoromethyi-benzyloxyimino)-ethyl]ethyl~benzyi}«azetidine carboxylic acid or a pharmaceutically acceptable salt thereof e.g. a hemifumarate salt and one or more non-basic ents. The 1-{4-{1-(4-cyciohexyl-B—tritluoromethyl- benzyloxyimino)—ethyl]—2—ethyl—benzyl}-azetidine-3—carboxylic acid or salt in a particular implementation is in the form of particles which have an X90 diameter of from 10 pm to 200 um and/or which are at least 80% lline. The ssed mixture may include a ant and/or be coated with a re barrier (eg. both includes a desiccant and have a moisture barrier coating).

The ceutical compositions of the present invention may be used to treat autoimmune diseases, eg. rheumatoid arthritis, systemic lupus erythematosus, Hashimoto’s thyroiditis and multiple sis, amongst many others, eg. as disclosed in W02004I103306 and US 200910036423 for example in paragraphs {0041340042} of US 036423. The pharmaceutical compositions of the present invention may be used to treat peripheral neurapathies, for example motor neuron disease, Guillain-Barre syndrome (GBS), chronic inflammatory demyeiinating polyradiculoneuropathy (ClDP), multifocal motor neuropathy with conduction block (MMN), or paraproteinaemic demyelinating peripheral neuropathy (PDN). in particular embodiments, the compositions of the invention are used to treat multiple sclerosis. The invention therefore includes a method for treating a t in need thereof, eg. having or suspected of having one of the aforesaid diseases, eg. multiple sclerosis, comprising administering to the patient a composition of the invention. The composition is desirably administered in an effective amount. Also disclosed are compositions of the invention for use in ng at least one of the aforesaid diseases, eg. le sclerosis.

Brief description of the Figures Figure 1 is a box plot which demonstrates the effect of drug particle size on the content uniformity of a tablet comprising 5 mg (equivalent base weight) of the hemifumarate salt of 'l —{4-[1~(4~cyclohexyi—3~trifluoromethyi~ benzyloxyimino)-ethyl]—2~ethyl—benzyl}—azetidins—3— carboxylic acid.

Figure 2 is a box plot which demonstrates the effect of drug particle size on the content uniformity of a tablet comprising 0.25 mg (equivalent base weight) of the hemifumarate salt of 1—{4-[1—(4-cyclohexyltrifluoromethyl- benzyloxyimino)-ethyl]ethyl-benzyi}~azetidine—3- yiic acid.

Figure 3 is a line graph which compares the sum of degradation products of four different compositions, each sing 0.25 mg (equivalent base weight) of the hemifumarate salt of 1 {4-11 -(4-oyciohexyl-S-trifluoromethyl- benzyloxyiminoyethyli-Z-ethyl—benzyl}-azetidine~3— carboxylic acid mixed with a lubricant.

Detailed descrigtion of the invention For the avoidance of doubt, it is hereby stated that the information disclosed earlier in this specification under the heading round to the Invention” is relevant to the invention and is to be read as part of the disclosure of the ion.

Throughout the description and claims of this specification, the words “comprise" and in” and variations of them mean “including but not limited to", and they are not intended to (and do not) exclude other es, additives, components, integers or steps.

Throughout the description and ctaims of this specification, the singular encompasses the plural unless the t otherwise requires. ln particuiar, where the indefinite articie is used, the specification (which term asses both the description and the claims) is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the ion are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification ding any accompanying claims, abstract and drawings), andlor all of the steps of any method or process so sed, may be combined in any combination, except combinations where at least some of such features and/or steps are-mutualiy exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features sed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so sed.

The term “treat” includes: (1) preventing or delaying the appearance of al symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be ted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) ting the state, disorder or condition (9.9., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical m thereof); and/or (3) relieving the condition (ta, causing sion of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a ment is administered to a patient to treat a disease, the outcome may not always be ive treatment.

“Effective amount" means an amount of an API or pharmaceutical composition sufficient to result in the d therapeutic response. The therapeutic response can be any response that a user (e.g., a clinician or patient) will recognize as an effective response to the therapy.

The invention relates to oral pharmaceutical compositions comprising as an API an S‘lP receptor modulator or agonist, eg. a compound of formula A1 or A2 as defined above. The disclosure describes solid phase dosage units, which may be a tablet or capsule, particularly a tablet. Exemplary compositions, e.g. tablets, contain 10mg or less of the AP! (equivalent base weight), e.g. 7.5mg or less of the API, for e 5mg or less of the API. Some solid phase dosage units, eg. s, contain 0.1mg or more APl (equivalent base weight), eg. 0.2mg or more of the API, for example 0.25mg or more APl. There are therefore included in the invention dosage units, eg. tablets, which contain from 0.1 mg to 10mg of the API (equivalent base ), e.g. 0.2mg to 7.5mg of the APl; particular dosage units, eg. tablets, contain from 0.25mg to 5mg of the APl (equivalent base weight), for example 2.5mg to 5mg of the APl. in one implementation of the invention, the dosage units (eg. tablets) contain no more than 4mg of the PM alent base weight), eg. from 0.2mg or 0.25mg to 4mg of the API.

Some dosage units contain from 2mg or 2.5mg to 4mg of the AP! (equivalent base weight). in one embodiment, the dosage units (e.g. tablets) contain 4mg of the AP!. ln one embodiment, the dosage units (eg, tablets) mentioned in this paragraph comprise, or consist of, a soiid phase mixture consisting of AP! and non-basic excipients which comprise a cellulosic ent, eg. selected from microcrystalline ceiiutose, hypromeilose, ethylcellulose and combinations thereof. ln another embodiment, the dosage units (eg. tablets) mentioned in this paragraph comprise, or consist of, a solid phase e consisting of AP! and non~basic ents which comprise acontrolled reiease material, eg. a non— basic hydrogei—former such as, for example, hypromeliose. The solid phase mixture have at least one coating. ln one embodiment, the compound is of formuia A1. it will be understood that this embodiment, like all embodiments mentioned herein, is applicable across the entire scope of the disclosure, inciuding to all other embodiments disctosed , including those disclosed in the following paragraphs. in one embodiment, R5 is H. in one embodiment, A is COORs, and in particular is COOH. in one embodiment, Z is in one ment, A-Z is in one embodiment, Y is phenyi optionally substituted by 1, 2 or 3 ls selected from halogen, N02, 01.6alkyl, Cmalkoxy; ham—substituted C1.6alkyl and hob-substituted C1-5alkoxy, and in particuiar Y is phenyl substituted by a single said radical, eg. by a single 01.3 alkyi radical. The designation “01.6” means “having 1, 2, 3, 4, 5 or 6 carbon atoms” and an ary 01.5 alkyl radical is ethyl. in one embodiment, A—Z-C(R4)(R3)—Y- is 0 R7 where R; is H, halogen, N02, Cisalkyl, Omalkoxy; halo-substituted {31.5alkyl and halo— substituted Cmalkoxy, and in particular is Cysalkyl eg. ethyl. in one ment, W is C1, 02 or C3 alkylene, particularly methylene; Since every embodiment disclosed herein is applicable to the entire disclosure of the invention, it will be understood that in this case (where W is 01, C2 or 03 alkylene, particularly ene), the compound may be of the formula A1 andior Y may be an optionally substituted phenyl group as previously described herein and in ular where A—Z—C(R4)(R3)-Y— may be 0 R7 In one embodiment (for example applicable to the embodiments mentioned in the immediately preceding paragraph), R1 is phenyl substituted by phenyl or by (33-08 cycloalkyl, e.g. by cyclohexyl, wherein each phenyl and cyciohexyl are each independently optionally substituted by 1 or2 substituents selected from n, C1.salkyi, 01.5alkoxy and halo substituted5alkyl or ~015alkoxy. R1 may therefore be phenyl substituted by 03-03 cycloalkyl, each optionally substituted as just mentioned; in one sub—embodiment, phenyl of R1 is substituted by a single substituent, eg. fluoro or in ular trifluoromethyl, and cycloalkyl of R1 is unsubstituted cyclohexyl. ln an ment where the compound is of formula At, phenyl is 1,4—substituted by W and cycloalkyl (eg. unsubstituted cyciohexyl).

The ation “Cg-C3” means having 3, 4, 5, 6, 7 or 8 carbon atoms, eggs 5 or 6 carbon atoms. in one embodiment, the compound is of formula A1; W is Ci, CZ or OS alkylene; Y is a phenyl group optionally tuted by 1, 2 or 3 radicals ed from halogen, N02, Ci.5alkyl, C1. salkoxy; halo—substituted 01.5alkyl and halo—substituted 01.5alkoxy; and R1 is phenyl substituted by C3-Cg cycloalkyl, wherein phenyl and exyl are each independently optionally substituted by 1 or 2 substituents selected from n, 01.5alkyl, C1.5ali<oxy and halo substituted-(31.5alkyl or -C1.6all<oxy.

Pharmaceutical compositions The invention in its various aspects is in part predicated on a g that an active compound as disclosed above, namely the marate salt of 1—{4-{1v(4wcyclohexyl*3— triflLioromethyl—benzyloxyimino)-ethyl]—2—ethyl-benzyl}-azetldine~3-carboxylic acid, has poor stability in certain settings and that stability of the compound in a pharmaceutical composition may be improved by ng one, two or three of the following measures: a not exposing the active compound to a basic compound, eg. excluding basic compounds from the ition (other than the active compound itself when in basic form) 6 having the active compound in the form of particles having a crystallinity of 80% or more . having the active nd in the form of particles having an X90 diameter of at least 8pm, e.g. at least 10pm. it will be appreciated that the hemifumarate salt of t~{4-{‘l~(4-cyclohexyl-S—trifluoromethyl- benzyloxyimino)-ethyl]~2~ethyl~benzyl}-azetidinecarboxylic acid is a representative of the compounds of formula A1 or A2 as described above and that the just—mentioned measures may therefore be beneficially applied to any such nd as an active pharmaceutical ingredient (APl) of a composition. ageously, the composition is substantially dry, egg. is made of substantially moisture- free tutents, and is provided with a moisture—protective layer as a barrier to ingress of water and/or includes a desiccant. in one implementation of the invention, the composition, for example in the form of a tablet, comprises a desiccant. in another implementation of the invention, the composition, for example in the form of a tablet, is provided with a moisture-protective layer. In a ular implementation, the composition, for example in the form of a tablet, comprises a desiccant and is provided with a moisture-protective layer. 2012/050151 it is advantageous to combine two or more of the above measures. For example embodiments of the invention lie in solid phase compositions, for examples capsules or tablets, particularly tablets, having one the following characteristics (1) to (6): (1) the API is not exposed to basic compounds, eg. basic compounds are excluded from the composition, and the API is in the form of particles having a crystallinity of 80% or more; (2) the AP! is not exposed to basic compounds, e.g. basic compounds are excluded from the ition, and the APl is in the form of particles having an X90 diameter of at least 8pm e.g. at least 10pm; (3) the APl is in the form of particles having an X90 diameter of at least 8pm eg. at least mum and a crystallinity of 80% or more; (4) the API is not exposed to basic compounds, eg. basic compounds are excluded from the composition, and the API is in the form of particles having an X90 diameter of at least 8pm eg. at least ‘lOum and a crystaiiinity of 80% or more; (5) any of (1), (2), (3) and (4) in combination with inclusion of a desiccant in the composition; (6) any of (t), (2), (3), (4) and (5) in ation with provision of a moisture-protective layer or coating. in particular, the above-mentioned APIs have poor stability in admixture with one or more of the following compounds; sodium starch giycolate (sold under the trade mark el®), sodium lauryl sulfate, ium te, calcium stearate, caicium carbonate, calcium sulfate, sodium stearyl fumarate and sodium bicarbonate. The above-mentioned APls also have poor stability in admixture with gelatin.

Not exposing the active compound to a basic compound may be achieved by not having the active compound in admixture with a basic nd. in an embodiment, ore, the AP! is in a mixture of materials which is free of basic compounds. Conveniently, therefore, the composition is free of basic nds. However, the invention includes, for example, the provision of two» or multi-part compositions of which one part incorporates a nd of formula A1 or A2 but is free of any basic compound and a second part does not incorporate a compound of formula A1 or A2 but does incorporate a basic compound. it will be tood that the expression “tree of any basic compound" and similar expressions do not mean that no base may be present in the composition but does allow very low amounts of base to be present, such an amount therefore being at a concentration which does not for practical purposes promote degradation of the API, For example, a basic compound may be an impurity which it is not possible or practicable to remove entirely or to an undetectable level. in embodiments, moiety A is not in the form of a salt but R5 is present as H or an ester— forming group R5 particularly is present as H (is. moiety A is in its acid form and not as a salt).

In one embodiment the pharmaceutical composition comprises a solid phase mixture, which may be in the form of a , and which consists of a nd of a A1 or A2 in ure with one or more non-basic compounds. The one or more non-basic compounds may comprise or consist of non—basic excipients, e.g. selected from: binders, disintegrants, glidants, lubricants, fillers, diluents, controlled e agents and sorbents. The composition, e.g. tablet, may have one or more coating layers and/or may have an basic component separated from said solid phase mixture by a barrier. Said solid phase mixture may comprise one or more non-basic APls in addition to one or more APls of formula A1 or A2. The composition, e.g. tabiet, may have a coating layer which is a moisture barrier, for example as sold under the trade mark Opadry® amb. A moisture barrier film composition is described in W01996I001874, included herein by reference for all purposes, and comprises potyvinyl alcohol, soya in, and optionally a flow aid, a colorant, and/or a suspending agent. Conveniently, the composition includes a desiccant, e.g, colloidal silica. in one embodiment the pharmaceutical composition comprises a solid phase mixture, which may be in the form of a tablet, and which consists of a nd of formula A1 or A2 in ure with excipients selected from e (e.g. as lactose monohydrate); microcrystalline ose; non-basic polymers e.g. homopolymers of cross-linked N—vinyl—Z— pyrrolidone (crospovidone), hypromellose (hydroxypropylmethyl cellulose), and ethyl cellulose; waxes; colloidal silicon dioxide; stearic acid; hydrogenated vegetable oii; mineral oil; polyethylene glycol (e.g. polyethylene glycol 4000—6000); gyceryl palmitostearate; and glyceryl behenate. in such a ation, e is considered to act as a filler, microcrystalline cellulose as a binder, crospovidone as a disintegrant, hypromellose and ethyl cellulose as a controlled release agent, dal silicon dioxide as a glidant and the remaining materials as lubricants; in embodiments, only a single such lubricant is included in the composition, eg. glyceryl behenate. Colloidal silicon dioxide acts also as a desiccant.

Hydrogenated ble oiismay act as controlled release agents. in one embodiment, the pharmaceutical composition comprises, or consists of, a solid phase mixture ting of AP! and non—basic excipients which comprise a celluloslc excipient, e.g. selected from rystalline cellulose, hypromeiiose, ethylcellulose and combinations thereof. in another embodiment, the ceutical composition comprises, or consists of, a solid phase mixture consisting of AP] and non—basic exclpients which comprise a controlled release material, eg. a sic hydrogel-former such as, for example. ellose. The solid phase e may have at least one coating.

An embodiment of the invention therefore ses a solid phase mixture, which may be in the form of a tablet, and which consists of a compound of formula A1 or A2 in admixture with: lactose (eg. as lactose monohydrate); rystalline cellulose; a polymer selected from homopolymers of cross—linked l-Z—pyrrolidone (crespovidone), hypromelloses, and ethyl cellulose; waxes, colloidal silicon dioxide; and a lubricant selected from stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol (eg. hylene glycol 4000-6000), l palmitostearate and glyceryi behenate, and combinations of the aforesaid lubricant compounds. For example, such an embodiment may comprise a solid phase mixture, which may be in the form of a tablet, and which consists of a compound of formula A1 or A2 in ure with: lactose leg. as lactose monohydrate); microcrystalline cellulose; a polymer selected from homopolymers of linked N-vinyl~2-pyrrolidone {crospovidone) and hypromelloses; colloidal silicon dioxide; and a lubricant selected from hydrogenated vegetable oil, mineral oil, polyethylene glycol (eg. polyethylene glycol 4000— 6000), gyceryl palmltostearate and glyceryl behenate, and combinations of the aforesaid lubricant compounds. In embodiments, a single lubricant is present in the solid phase mixture, particularly glyceryl behenate.

W0 20121093161 Eadie/2.81:9. it will be recalled that an aspect of the invention is in part predicated on a finding that the stability in a solid phase ition, particularly a tablet, of an active compound as disclosed above, namely the hemifumarate salt of 1—{4~[1-(4-cyclohexyl~3—trifiuoromethyl- benzyloxyimino)~ethyl}-2‘-ethyl—benzyl}~azetidine—3scarboxylic acid, may be improved by the active compound being in a relatively large particle size but, in most instances, a particle size not so large that the composition fails to comply with the the USP, EP and JP harmonised content mity requirement, eg. as in force on 1 January 2011. it will be appreciated that the hemifumarate salt of 1-{4vi1~(4~cyclohexyl—3-trifluoromethyl- benzyloxyimino)—ethyi]~2—ethyl~benzyl}-azetidine-3~carhoxyiic acid is a representative of the compounds of formula A1 or A2 as described above and that the just-mentioned measures relating to particle size may therefore be beneficially applied to any such compound as an active pharmaceutical ingredient (APl) of a composition. The invention therefore provides a solid phase ation, particularly a tablet. comprising a compound of formula A1 or A2 in a relatively large particle size, eg. an X90 diameter of at least 8pm and often of 10pm or more, for example 20pm or 25pm or more, optionally of 100pm or more and r optionally of 150nm or more. The particle size (X90 diameter) may be up to 300nm, eg. up to 250nm, and optionally up to ZDOpm (eg. up to 195pm). in some embodiments, the X90 er is of from 10pm to BOOum, eg. 10pm to 250nm or 10pm to 200nm, Also included are ments in which the particle size (X90 diameter) is from 25pm to 300pm, eg. 25pm to 250nm or 25pm to ZOOum. Further included are embodiments in which the X90 diameter is from 100pm to BOOum. ego ‘lOOpm to 250nm or 100nm to 200nm. in a particular embodiment, the X90 particle diameter is at least 10 um and is less than 191nm, e.g. less than 180nm, less than 170 um, less than 160 pm, less than 150 pm, less than 140 pm or less than 130 pm, eg. no more than 125 pm, such as no more than 121 pm; in a sub— embodiment, the X90 le diameter is at least 25 pm and is less than 191pm, eg. less than 18Gum, less than 170 pm. less than 160 pm, less than 150 um, less than 140 pm or less than 130 pm, eg. no more than 125 pm, such as no more than 121 pm. in some instances the X90 particle diameter is at. least 10 pm or 25 pm but no more than 100pm, eg. is no more than 90pm, no more than 80pm, no more than 70pm, no more than 60pm, no more than 50pm or no more than 40pm, for example is no more than 30pm. in other W0 2012f093161 embodiments, the X90 particle er is from 121pm to 191nm. in another embodiment, the X90 particle diameter is from 11pm to 29pm.

An aspect of the invention is in part predicated on a finding that, in the case of an APl of formula A1 or A2, AP! particles of the sizes mentioned herein of at least 8pm may be formulated into tablets which have a tablet content uniformity which fulfills the requirement of the USP, EP and JP harmonised content uniformity requirement. in particular as in force on 1 January 2011. The pharmaceutical compositions of the present invention may , and desirably do fulfill, the USP, EP and JP harmonised content uniformity requirement (refer to chapter 2.9.40. Uniformity of dosage unit in the EP). A maximum le size which enables the requirement to be met cannot be stipulated e the maximum possible les size varies with the drug content of the dosage unit. For example, in the case of a tablet containing 0.25mg of an APl (equivalent base weight), APl particles having an X90 diameter of 121pm compiled with the harmonised content mity requirement whereas APl particles having an X90 diameter of 19ipm failed to comply. in contrast, in the case of a tablet containing 5mg (equivalent base weight), of an AP], AP! particles having an X90 er of up to 191nm complied with the harmonised content mity requirement. A maximum particle size which enables any particular tablet composition to meet the harmonised t uniformity requirement may be determined empirically.

The particle size bution (by voiume) may be measured using a laser diffraction sizing instrument, for example the Sympatec Helcs device (available from Sympactec GmbH, Germany) using the Cuvette dispersion device. The X90 diameter is the spherical er corresponding to the ng volume.

To make the measurement, a stock dispersion may be prepared by mixing the drug substance with a dispersing aid {eg Octastat 5000 (Octal corp» using a vortex until a smooth and homogeneous paste is formed. The paste may then be diluted and mixed to a final volume of 3 to 6 ml using white spirit. The optical concentration of the final solution should remain below 5%. The percent values are calculated from the mean tive volume size curve by the re of the Sympatec instrument. X90 mean 90% of the particle size population is below the specified value in volume.

Additional confirmatory information on particle size may be obtained using SEM (scanning electron microscopy).

Content uniformity g is used to test the active content within individual units post- manufacturing (such as the t of active agents within individuai s after compression) .

Content uniformity is influenced by the le size of the drug substances. Median particie size is denoted by Xm, where m is a percentage of the particle size distribution.

The invention includes the following embodiments (optionally in combination with the features of other embodiments disclosed herein): 1) a solid phase pharmaceutical composition in unit dosage form which comprises one or more pharmaceutically acceptable excipients, in particuiar non-basic excipients, and an APl as described herein and which complies with the US Pharmacopeia, European Pharmacopeia and Japanese Pharmacopeia harmonised t mity requirements as in force on 1 January 2011; 2) a tablet which comprises one or more pharmaceuticaiiy acceptable excipients, in ular non—basic excipients, and an AM as described herein in an amount of from 4 mg to 8mg APl (equivaient base weight), the APl being as particles have an X90diameter of at ieast iOOpm butno more than 300nm, ago from iOOpm to 250cm, from toopm to 200nm, from 100nm to 190nm, from 100nm to iBme, from 100nm to tTOpm, from 100nm to 160pm or from 100nm to iSOum; 3) a tablet which comprises one or more pharmaceuticaliy acceptable excipients, in particular nonabasio ents, and an AP! as described herein in an amount of from from 0.2 mg to 1 mg APl (equivalent base weight), the API being as particles have an X90 diameter of at least 10pm but no more than 100nm, e.g. 10pm to 90pm, 10pm to 80pm, 10pm to 70um, 10pm to 60pm, 10pm to 50pm, 10pm to 40pm or 10pm to 30pm.

An aspect of the invention resides in compounds of formula A1 or A2 when in ulate form having an X90 diameter as disclosed herein, as well as products or compositions of matter comprising such particulate compounds.

Cflstaflinitz The invention is in part also predicated on a finding that the stability in a solid phase formulation, ularly a , of an active compound as disclosed above, namely the marate salt of 1-{4—[i~(4—cyclohexyl-3~trifluoromethyl-benzyloxyimino)~ethyl]-2~ethyl— benzyl}~azetidinecarboxylic acid, may be enhanced by the active compound being in particles of relatively high crystallinity, eg. a crystallinity of 80% or more, for example 85% or more and optionally of 90% or more. it will be appreciated that the above salt of l~{4—[1—(4~cyclohexyl-B—trifluoromethyl~ benzyloxyimino)-ethyl]-2ethyl—benzyl}azetidine—3-carboxyiic acid is a representative of the compounds of formula A1 or A2 as described above and that the just—mentioned measures may ore be beneficially applied to any such compound as an active pharmaceutical ingredient (APl) of a composition. The invention therefore provides a solid phase ation, particularly a tablet, comprising a compound of formula A1 or A2 in a crystallinity of 80% or more, for example 85% or more and optionally of 90% or more.

An aspect of the invention resides in compounds of a A1 or A2 when having a crystallinity of 80% or more, for example 85% or more and optionally of 90% or more, as well as products or compositions of matter comprising compounds having such llinity.

Conveniently, a crystallinity of 80% or more may be attained by a compound of a A1 or A2 being as particles having an X90 diameter of 10pm or more and particularly 11pm or more, for example 20pm or 25pm or more, optionally of iOOpm or more and further optionally of 150pm or more. The X90 diameter may be as previously described herein under the g “Particle Size”.

Crystallinity may be measured using any suitable means, for example using X-ray powder diffraction (XRPD), for example using a Broker D8 device, WO 3161 it wiil be iated that solid phase compositions, e.g. tablets, may advantageously combine the features of particle size and/or crystallinity disciosed herein with the feature of not exposing the AP! to a basic compound.

Methods for making the pharmaceutical compositions Compositions of the ion may ty be made by combining the components as dry powders, for example tablets may be made by dry granulating the components of the tablet mix and ally applying a film coating, for example a moisture r film, to the compressed tablet.

APl particles can be prepared by suitable milling techniques, eg. those wetl known in the art such as, for example, wet—jet mitiing, pin-milling, and wet-ball milling Where the APE particles are derived from coarse APi particle crystals, the coarse crystals may be ed using any suitable methodolgy. For e any of the methodologies set out in W020101071794, W02010!080455 or W02010/080409.

Of interest in the invention are the foiiowing numbered paragraphs, 1. A solid phase pharmaceuticat composition comprising one or more pharmaceutically acceptable exoipients and an active pharmaceutical ingredient (“API”) which is a compound of formula At or A2 or a pharmacologicaily acceptable satt, solvate or hydrate thereof, wherein the APl is not exposed to a basic compound: A": fir i 33’ “2 N Y\w/O\N)\R1 A1 A2 wherein A is 000%, OPO(OR5)2, PO(OR5)2, SOZORs, PORsoRs or 1H-tetrazolyl, R5 being H or an ester—forming group; WO 93161 W is a bond, C1.3ail<ylene or 02.3alkenylene; Y is 05.10am or Caegheteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, N02, 01.5alkyl, xy; halo—substituted 01-5alkyi and halo-substituted l<oxy; Z is chosen from: \/’*; \v/Vm , ”EVER/1e; *\'¥/\* *\ \/://*’ R6 R6 R6 R5 *._ (>— , \ri/Y ; \N , \N/W , R5 OH N\/\* N\/\* ['26 F F 1: it I * a!» \i we a»*at *i R5 F */N * * R6 *I * T R6 \RES/0* W O 9: l N N I HO NV/\*; k/i */ HQ N\/\* * ,*/\ A/ {PW;‘k '1: /k/‘k 1, i‘ _ \N , ,and \N * \IE‘J \fi‘g J2 $6 R6 l R6 R5 R5 9: wherein the asterisks of Z indicate the point of attachment between -C(R3)(R4)— and A of Formula la or lb, respectiveiy; R5 is chosen from hydrogen and Cmalkyl; and J1 and J2 are independently methylene or a heteroatom chosen from S, O and NR5; wherein R5 is chosen from hydrogen and Cmalkyl; and any alkylene of Z can be further tuted by one to three radicals chosen from halo, hydroxy, C1.5alkyl; or R; can be attached to a carbon atom of Y to form a 5-7 member ring; R1 is 05.1oaryl or theteroaryl, optionally ”substituted by C1_6all<yl, 05.10am, Ce1oarleMalkyl, Cegheteroaryl, 03-9heteroarinMalkyl, Cs.goycloalkyl, CmcycloalkleMalkyl, C3.3heterocycloalkyl or theterocycloalkinMalkyl; n any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R1 may be substituted by 1 to 5 groups selected from halogen, Ci, ealkyl, xy and halo substituted—01.5aikyl or -C1.5alkoxy; R2 is H, C1-5alkyl, halo tuted Omalkyl, Cgaaikenyl or Cg.saii<ynyl; and each of R3 or R4, independently, is H, halogen, OH, Cmalkyi, Ctaalkoxy or halo substituted Smalkyl or C1.ealkoxy. 2. A composition of numbered paragraph 1 wherein A is COOH. 3. A composition of numbered paragraph 1 or 2 wherein the compound is of formula A1. 4. A composition of numbered paragraph 3 n: W is Ci, 0; or C3 alkyiene; Y is a phenyl group optionally substituted by 1, 2 or 3 radicals selected from halogen, N02, C1_5alkyl, koxy; halo-substituted Cmalkyl and halo-substituted xy; and R1 is phenyi substituted by 03-68 cycioalkyl, wherein phenyi and cyciohexyl are each independently optionally substituted by 1 or 2 substituents selected from halogen, Cifialkyl, Ci.salkoxy and halo substituted-C1.salkyl or -Ci.saikoxy.

. A composition of numbered paragraph 1 wherein the APi is 1—{4—{1-(4-cyclohexyI—3- romethyi-benzyioxyimino)—ethyl]~2~ethyl-benzyi}—azetidine—3-carboxylic acid or a pharmaceutically acceptable salt. 6. A composition of numbered paragraph 1 wherein the APi is 1-{4-[1-(4-cyclohexyl—3- romethyl~benzyloxyimino)—ethyl}-2—ethyl—benzyl}~azetidine-B-carboxylic acid or a hemifumarate sait thereof. ‘7. A composition of any preceding numbered paragraph wherein the API is in a mixture of materials which is free of basic nds. 8. A composition of any preceding numbered paragraph which is a tablet.

W0 2012f093l61 8. A ition of numbered paragraph 8 wherein the tablet is coated with a moisture to. A composition of numbered paragraph 8 or 9 wherein the tablet ses a soiid phase mixture which consists of the API in admixture with: lactose; microcrystalline celtuiose; a polymer selected from homopoiymers of cross-linked N-vinyl-Z-pyrrolidone (crospovidone) and elloses; colioidal n dioxide; and a iubricant selected from hydrogenated vegetable oii, mineral oit, polyethyiene glycol, gyceryl palmitostearate and yi behenate. 11. A solid phase pharmaceutical ition comprising one or more pharmaceuticaiiy acceptable excipients and an active pharmaceuticat ingredient (“APl”) selected from the compounds as defined in any of numbered aphs 1 to 6, wherein the API is in the form of particles having an X90 diameter of at least 8pm, 12. A composition of numbered paragraph 11 wherein the particles have an X90 diameter of from 10pm to 300nm. 13. A composition of numbered paragraph 12 wherein the les have an X90 diameter of at least term but no more than locum. 14. A composition of numbered paragraph 12 wherein the particies have an X90 diameter of at least 100nm but no more than 250nm.

. A composition of any of numbered paragraphs 11 to 14 which is in unit dosage form and complies with the US Pharmacopeia, European Pharmacopeia and Japanese Pharmacopeia harmonised content uniformity requirements as in force on 1 January 2011. 16. A composition of numbered paragraph 15 which is in the form of a ’containing from 4 mg to 6mg AP! (equivalent base weight) and particles have an X90 diameter of at least toopm but no more than 200nm. 17. A composition of numbered paragraph 15 which is in the form of a tablet containing from 0.2 mg to 1 mg APi (equivalent base weight) and particles have an X90 diameter of at ieast 10pm but no more than 50pm. -24_ 18. A composition of any of numbered paragraphs 11 to 17 which further includes the features of any one of, or any combination permitted by dependency of, of numbered paragraphs 1 to 10. 19. A solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable ents and an active pharmaceutical ingredient (“APl”) selected from the compounds as defined in any of numbered paragraphs 1 to 6, wherein the API has a crystallinity of 80% or more.

. A composition of numbered paragraph 19 wherein the APl has a crystallinity of 85% or more. 21. A composition of numbered paragraph 19 or 20 which is a tablet. 22. A composition of any of numbered paragraphs 18 to 21 which further includes the features of any one of, or any combination ted by dependency of, of numbered paragraphs 1 to 10 and 11 to 17. 23. A tablet comprising a compressed mixture consisting of 1~{4—[1~(4—cyclohexyl«3- trifluoromethyl—benzyloxyimino)—ethyll-Z—ethyl«benzyl}~azetidine—3-carboxylic acid or a pharmaceutically able salt thereof and one or more non-basic ents, the 1~{4-[1- (4-cyclohexyl—3~trifluoromethyl~benzyloxyimino)~ethyl}~2—ethyl—benzyl}~azetidine-3~carboxylic acid or pharmaceutically acceptable salt being in the form of particles having an X90 er of from 10 pm to 200 pm. 24. A tablet of numbered paragraph 23, n the pharamaoeuticaily acceptable salt is a hemifumarate salt.

. A tablet of numbered paragraph 23 or 24 wherein said particles are at least 80% crystalline. 26. A tablet of numbered aph 23, 24 or 25 n the compressed mixture includes a desiccant and is coated with a moisture barrier.

W0 2012(093161 Examples Examgie 1 The following Exampie illustrates the stability of the hemifumarate salt of 1 ~{4~[1-(4- cyciohexyltrifluoromethyl-benzyloxyimino)-ethyi]-2—ethyi~benzyi}—azetidine—3—carboxyiic acid in the presence of various compounds. Mixtures of this APE with various compounds were d in a sealed viai to conditions of 50°C temperature and 75% relative humidity for 4 weeks. After 4 weeks, the AP! degradation and sum of degradation products were d. The results are dispiayed in Table 1.

Assay method: HPLC using agilent 11000 and a Phenomenex Gemini C18 column. UV detection at 260 nm was used. The mobile phase used was a gradient water— acetonitriie containing 0.2% (v/v) formic acid and 10% (v/v) Triethyiamine.

The hemifumarate salt of 1—{4—[1-(4-cyciohexyi~3-tfifiuoromethyl-benzyloxyimino)-ethyi]-2— benzyl}-azetidinecarboxyiic acid is described as "NVS- ” in Table 1.

Table 1 Mixture Sum of unknown peaks (%)* Assay (%)* NVS-A aione 1.86 100.2 NVS~A 4- Lactose (1 :1) 1.74 96.5 NVS-A + Maize Starch (1:1) 1.82 99.4 NVS—A + Microcrystaiiine Ceiiuiose 1.80 99.0 (1 :1) NVS-A + ol (1:1) 1.80 99.2 NVS-A + HPMC (1:1) 2.45 97.7 NVS~A + PVP K30 (1:1) 2.07 99.6 NVS~A + Ac~Di~Soi (1:1) 1.89 99.7 NVS-A + Primojei (1:1) 4.08 100.9 NVS~A + Crospovidone (1 :1 ) 1.89 99.7 NVS-A + Mgstearate (1 :0.85) 0.31 98.2 NVS-A + Mg te (1 :0.85)* 3.68 90.0 NVS—A + Sodium LaurylSuifate (8L8) + 8.54 88.3 Microcrystaiiine Ceiiuiose (2:1 :1) - 25 _ Mixture Sum of unknown peaks (%)* Assay (%)* NVS—A + Gelatin (1:1) 3.86 96.1 NVS—A + Aerosil 4- Miorocrystalline 1.89 99.9 ose {2:1 :1) NVS—A + Magnesium Stearate (Mg St) 6.13 89.2 + Miorocrystalline Cellulose (221:1) NVS-A + Magnesium stearate + 10.53 80.7 Microcrystalline Cellulose (2:1 :1 NVS-A + Magnesium stearate + lactose 9.31 82.2 {2:1 :1) NVS-A + Calcium stearate + 4.55 89.8 Microcrystalline Cellulose (2:1:1) NVS—A + sodium stearyl fumarate + 752 83.1 Microorystalline Cellulose (211:1) NVS-A + Sodium bicarbonate + 8.48 61.8 rystalline Cellulose (2 :1 :1) NVS-A + Tween 80 + rystalllne 2.07 100.1 Cellulose (2:1 :1) * at 50°Cf75%RH opened vial/ 4 weeks Examgle 2 The following Example demonstrates the detrimental effect of magnesium stearate on the hemifumarate salt of 1{ti—{1—(4~cyolohexyl—3-triiluoromethyl-benzyloxyimino)-ethyl1—2—ethyl- benzyl}azeticiine-3—carboxyllo acid (NVS-A).

A film coated tablet containing NVS-A was developed comprising micronised drug substance, e monohydrate, microcrystalline ose, crospovidone, colloidal silicon dioxide. and magnesium stearate. A moisture protective Opadry® AME film coating was applied. Tablet strengths from 0.25 mg to 5 mg (equivalent free base weight) were produced as shown in Table 2 below.

Table 2 Comgosition of the immediate release 0.25 and 5 mg tablet containing magnesium stearate as lubricant. ——————————-~—--————————————-—————__......______._._.._ ingredient Amount (mg) per Amount (mg) per Function Reference to 0.25 mg tablet 5 mg tablet standards Tablet core NVS-A 0.2781 5.5602 Drug substance Novartis monograph Lactose 63.897 58.615 Diiuent Ph. Eur. INF monohydrate rystalline 17.000 17. 000 t Ph. Eur. INF ose! Cellulose rystaiiine Crospovidone 2.550 2.550 Disintegrant Ph. Eur. INF Silica, colloidal 0.425 0.425 Gliding agent Ph. Eur. INF anhydrous I dal silicon dioxide Magnesium 0.850 0.850 Lubricant Ph. Eur. INF stearate Core tablet 85.000 85.000 weight Coating Coating premix 8.400 3.400 Coating agent Opadry AMB white" Water, purified" 13.600 13.800 Solvent Ph.Eur. IUSP Total film-coated 88.400 88.400 tablet weight 1Corresponds to 0.25 mg (8.9. 0.294% wIw) NVS-A base respectively BCorresoonds to 5 mg (eg 5.88% wIw) NVS-A base respectively * Removed during‘processing *" The qualitative composition of the coating premix is as follows: Coating premix ingredient Reference to standards Polyvinyl l - part ised PhEur. I USP Titanium dioxide PhEur. I USP Talc PhEur. / USP Lecithin (soya) NF Xanthan gum PhEur. I NF The tablets were only stable for prolonged periods at 2-8°C. At 25°C, the 0.25 mg strength tablet was stable for only 6 months and the 5 mg tablet was stable for only 12 months.

Beyond 6 months and 12 months at 25°C respectively for the 0.25 and 5 mg teblet,the stability data did not fulfill the stability guidance from the international Conference on ~28— Harmonisation of Technicai Requirements for Registration of Pharmaceuticals for Human Use (iCH).

Example 3 The effect of drug particle size on the content uniformity of a tablet comprising 5 {equivaient free base ) of the hemifumarate sait of 1-{4~[1-(4-cyciohexyi~3— trifluoromethyl-benzyioxyimino)—ethyi1-2~ethyi~benzyi}—azetidine~3~carboxylic acid (NV/SA) was studied.

The X90 particle size distribution (by volume) was measured using a laser ction sizing instrument [the Sympatec Heios device (avaiiabie from tec GmbH, Germany) using the e dispersion device: To make the measurement, a stock dispersion was prepared by mixing the drug substance with a dispersing aid tat 5000 (Octet corp» using a vortex until a smooth and homogeneous paste was . The paste was then diluted and mixed to a tinai volume of »3 to 6 ml using white spirit. The optical concentration of the final solution were kept below 5%. The percentage vaiues were calculated from the mean cumulative voiume size curve by the software of the Sympatec instrument. onai confirmatory information on particle size was obtained using SEMI (scanning electron microscopy).

The finer APl material (X90 < 10pm (4 and 7 pm) was obtained by micronisation using a jet mill [Hosokawa Alpine AFG100] using a re in the range from 2 to 5 bars. The material with X90 at 11, 29 um and 121 pm was obtained by miiiing in this case with a pin miii with the relative tin speed being adjusted from 115, to 75 to 40 mlsec respectively. Finaiiy, the coarser materiai with X90 pm of 191 um was obtained by sieving on a 457um sieve.

The results are presented in Figure 1.

The drug substance particle sizes considered showed reduced impact on the mean content uniformity value and its variability for the 5 mg tabiet: . where X90 = 191 pm, the content uniformity ranged from about 97.3% to about 104.0% a where X90 = 121 pm, the content uniformity ranged from about 92.8% to about 99.7% o where X90 = 29 pm. the content uniformity ranged from about 97.2% to about 102.9% a where X90 == 11 pm, the t uniformity ranged from about 97.3% to 100.1% a where X90 = 7 um, the content uniformity ranged from about 94.1% to 98.9% . where X90 = 4 um, the content uniformity ranged from about 93.3% to 99.1 %.

This study demonstrated that despite the low tablet strength, micronised drug substance (where X90 = 4 um to 7 urn) was not essentiai to fuifil the USP, EP and JP harmonised content uniformity requirement. This requirement could be achieved when using milled drug substance (where X90 = 11 um to 29 um) and aiso unexpectedly using the coarse drug substance (where X90 = 121 pm to 191 um).

Examgle 4 The effect of drug particle size on the content uniformity of a tablet comprising 0.25 (equivalent free base weight) of the hemifumarate salt of 1~(4-cyclohexyI-3— trifluoromethylbenzyloxyimino)-ethyli—Z-ethyi-benzyl}-azetidins-3‘carboxylic acid ) was d. APi drug particles were obtained and measured as in Example 3.

The results are presented in Figure 2.

Coarse drug substance with an X90 er of 121 um and 191 um led to a significant increase in content uniformity ility: a where'XQO = 191 pm, the content uniformity ranged from about 81.2% to about 113.9% a where X90 = 121 um, the content uniformity ranged from about 87.6% to about 106.5%.

Milled drug substance with an X90 of 11 pm or 29 um ted to a better centered mean content uniformity and a ly lower content variability than the one ed with the micronised drug substance (X90 = 4 and 7 um): e where X90 = 29 um, the content uniformity ranged from about 98.5% to about 101.6% a where X90 ‘2 11 um, the content uniformity ranged from about 98.9% to about 101.8% 0 where X90 = 7 pm, the content uniformity ranged from about 95.9% to about 102.2% a where X90 = 4 pm, the content uniformity ranged from about 94.0% to about 101.3%.

This example trates that despite the low tablet strength, micronised drug substance (where X90 = 4 pm to 7 pm) is not essential to fulfil the USP. EP and JP harmonised t uniformity requirement. This requirement can unexpectedly be achieved when using milled drug substance (where X90 = 11 pm to 29 pm). The upper limit that ed the USP, EP and JP harmonised t uniformity requirement was a 0.25 mg tablet with a particle size characterised by a X90 = 121 pm.

Example 5 The ing exempts compares the sum of degradation products of four different compositions, each comprising 025 mg (equivaient free base weight) of the hemifumarate salt of 1-(4-cyclohexyl-3—trifluoromethyl—benzyloxyimino)—ethyl]ethyl-benzyl}- azetidine-S-carboxylic acid (NUS—A) mixed with a lubricant. AP! drug particles were obtained and measured as in Example 3. The lubricants and the le sizes of each composition are as follows. The table below ises the difference in composition between the tablets made with magnesium stearate and giyceryl behenate as lubricant. it should be noted that the tablet made with glyceryl behenate and with the different drug substance particie size were not coated with the moisture protective film coated opadry AMB in order to better demonstrate the stability benefit. AP! drug particies were obtained and measured as in Table 3: Composition of the ate release 0.25 mg tablet (eguivalent free base weight) containing magnesium stearate and glycegyl behenate as lubricant. tngredient Amount (mg) per Amount (mg) per Function Reference to 0.25 mg tablet 0.25 mg tablet standards with magnesium with giyceryi sterate as behenate as iubricant iubricant Tablet core NVS—A 0.2781 0.27’81 Drug substance Novartis monograph Lactose 63.897 58.707 Diluent Ph. Eur. INF monohydrate Microcrystaltine 17.000 17.000 Diluent Ph. Eur. INF oellulose/ Cellulose microcrystailine Crospovidone 2.550 2.550 Disintegrant Ph. Eur. INF WO 93161 _ 31 - lngredient Amount (mg) per Amount (mg) per Function nce to 0.25 mg tablet 0.25 mg tablet standards with magnesium with glyceryl sterate as behenate as lubricant lubricant Tablet core Silica, colloidal 0.425 0.425 g agent Ph. Eur. INF anhydrous} Colloidal silicon dioxide Magnesium 0.850 0 Lubricant Ph- Eur. INF stearaie Glyceryl behenate 0 5.950 Lubricant Core tablet 85.000 85.000 weight Coating Coating premix 3.400 0 Coating agent Opadry AMB white“ Water, purified" 13.600 0 Solvent PhEur. fUSP Total film-coated 88.400 Not applicable tablet weight 1Corresponcls to 0.25 mg (eg. 0.294% w/w) NVS—A base respectively * Removed during processing ** The qualitative composition of the coating premix is as follows: Coating premix ingredient Reference to standards Polyvinyl alcohol ~ part hydrolised PhEur. ; USP um dioxide . f USP Talc PhEui’. / USP Lecithin (soya) NF Xanthan gum PnEur. / NF Pimp.“ Magnesium stearate, micronised drug substance X90 < 8 pm.

Glyceryl beheneie, micronised drug substance X90 < 8 pm.

Glyceryl behenate, milled drug substance X90 = it um.

Glyceryi behenate, milled drug substance X90 = 29 pm.

Each of the 4 compositions were stored at 40°C in 75% ve humidity. The evolution of degradation t for each composition was followed over a period of six months. The results are shown in Figure 3. 2012/050151 . Composition 1 exhibited around 16% degradation product after 3 months of storage.

. Composition 2 exhibited around 4% degradation product after 3 months of e. a Composition 3 ted around 2% degradation product after 3 months of e.

- Composition 4 exhibited around 1% degradation product after 3 months of storage.

These results demonstrate that replacing magnesium stearate with glyceryl behenate reduces the sum of degradation product. Furthermore, changing the drug substance quality from micronized (less than 80% orystallinity) to milled (greater than 80% crystallinity) also reduces the sum of degradation product. -33..

Claims (11)

What is claimed

1. A solid phase pharmaceutical ition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“APl”) which is 1-{4-[1-(4- cyclohexyltrifluoromethyl-benzyloxyimino)-ethyI]ethyl-benzy|}-azetidine~3~carboxy|ic acid or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein the APl is in a mixture of materials which is free of basic compounds, with the exclusion of basic forms of the API itself.

2. A composition of claim 1 wherein the API is 1-{4—[1-(4—cyclohexyItrifiuoromethyl- benzyloxyimino)—ethyl]—2-ethyl-benzyl}-azetidine-3—carboxylic acid hemifumarate salt.

3. A solid phase ceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“APl”) selected from the compounds as defined in claim 1 or 2, wherein the API is in the form of les having an X90 diameter of at least 8pm.

4. A composition of claim 3 wherein the particles have an X90 diameter of from 10pm to 300pm.

5. A composition of claim 3 or 4 which is in unit dosage form and complies with the US Pharmacopeia, European Pharmacopeia and Japanese copeia harmonised content uniformity requirements as in force on 1 y 2011.

6. A solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“APl”) ed from the compounds as defined in claim 1 or 2, wherein the API has a llinity of 80% or more and n the APl is in a mixture of materials which is free of basic nds, with the exclusion of basic forms of the API .

7. A tablet comprising a compressed mixture consisting of an active pharmaceutical ingredient (“API”) which is 1 -{4-[1-(4-cyclohexyltrif|uoromethyl-benzyloxyimino)-ethyl]—2- ethyl-benzyl}-azetidine—3—carboxylic acid or a pharmaceutically acceptable salt thereof and one or more non—basic excipients, the 1-{4-[1-(4—cyclohexyltrifluoromethyl- benzyloxyimino)-ethyl]-2—ethyl-benzyl}—azetidine-3—carboxylic acid or pharmaceutically acceptable salt being in the form of particles having an X90 diameter of from 10 pm to 200 um, wherein the 1-{4—[1-(4-cyclohexyl-3—trifluoromethyI—benzyloxyimino)-ethyl]ethy|— -34.. benzyl}-azetidinecarboxylic acid or a pharmaceutically able salt thereof is not in admixture with a basic nd, with the exclusion of basic forms of the API itself.

8. A tablet of claim 7, wherein the pharmaceutically acceptable salt is a hemifumarate salt.

9. A tablet of claim 7 or 8 wherein said particles are at least 80% lline.

10. A tablet of any one of claims 7, 8 or 9 wherein the compressed mixture includes a desiccant and is coated with a moisture barrier.

11. The ition of any one of claims 1, 3 or 6, substantially as herein described with reference to any one of the Examples and/or