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WO2012095853A1 - Formulations à libération modifiée comprenant des modulateurs des récepteurs sip - Google Patents

Formulations à libération modifiée comprenant des modulateurs des récepteurs sip Download PDF

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Publication number
WO2012095853A1
WO2012095853A1 PCT/IN2011/000020 IN2011000020W WO2012095853A1 WO 2012095853 A1 WO2012095853 A1 WO 2012095853A1 IN 2011000020 W IN2011000020 W IN 2011000020W WO 2012095853 A1 WO2012095853 A1 WO 2012095853A1
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WO
WIPO (PCT)
Prior art keywords
composition
api
alkyl
tablet
ethyl
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Ceased
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PCT/IN2011/000020
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English (en)
Inventor
Philippe BOUILLOT
Etienne PIGEOLET
Parag BORDE
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Novartis Pharma AG
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Novartis Pharma AG
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Priority to PCT/IN2011/000020 priority Critical patent/WO2012095853A1/fr
Publication of WO2012095853A1 publication Critical patent/WO2012095853A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/08—Antibacterial agents for leprosy

Definitions

  • the present invention relates to formulations of immunosuppressant compounds, and particularly to formulations of S1P receptor modulators. More particularly the invention relates to formulations of selective S1P1/S1P5 modulators, particularly 1- ⁇ 4-[1-(4-cyclohexyl- 3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, pharmaceutically acceptable salts, and related compounds.
  • S1 P receptors belong to a family of closely related, lipid activated G- protein coupled receptors.
  • S1P1, S1P3, S1 P2, S1P4, and S1 P5 are identified as receptors specific for sphingosine-1 -phosphate (S1P).
  • Certain S1P receptors are associated with diseases mediated by lymphocyte interactions, for example, in transplantation rejection, autoimmune disease, inflammatory diseases, infectious diseases and cancer.
  • WO2004/103306 discloses immunosuppressant compounds that are useful in the treatment
  • WO2010/020610 discloses use of S1 P receptor agonists, for example 1- ⁇ 4-[1-(4-cyclohexyl- 3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, in the treatment of peripheral neurapathies, such as Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CI DP), multifocal motor neuropathy with conduction block (MMN), and paraproteinaemic demyelinating peripheral neuropathy (PDN).
  • GBS Guillain-Barre syndrome
  • CI DP chronic inflammatory demyelinating polyradiculoneuropathy
  • MNN multifocal motor neuropathy with conduction block
  • PDN paraproteinaemic demyelinating peripheral neuropathy
  • WO2007/021666 discloses a concentrate for dilution comprising a S1 P receptor agonist, propylene glycol and optionally glycerin, which concentrate is described as being stable for extended periods of time.
  • One compound mentioned as an S1 P receptor agonist is 1- ⁇ 4-[1- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid.
  • the dilution disclosed in WO2007/021666 is provided in a liquid form and is therefore particularly suitable for patients who struggle to swallow solid medications.
  • compositions comprising S1 P receptor modulators, such as 2- substituted 2-amino-propane-1 ,3-diol or 2-amino-propanol derivatives, which are suitable for use as an oral dosage form.
  • S1 P receptor modulators such as 2- substituted 2-amino-propane-1 ,3-diol or 2-amino-propanol derivatives, which are suitable for use as an oral dosage form.
  • the composition is disclosed to comprise the active ingredient and one or more of various specified excipients.
  • Example 10 mentions glyceryl behenate as a non-feasible excipient, seemingly because of degradation of the active (FTY720).
  • One S1 P modulator metioned is 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2- ethyl-benzyl ⁇ -azetidine-3-carboxylic acid.
  • WO2010/072703 teaches that SIP receptor modulators or agonists may produce a negative chronotropic effect, i.e. reduce the heart rate.
  • a dosage regimen for minimising the negative chronotropic effect of an S1 P receptor modulator e.g. when used for the treatment of patients suffering from an autoimmune disease, for example multiple sclerosis.
  • the dosage regimen comprises administering a lower dosage of an S1 P receptor modulator 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 S1 P receptor modulator.
  • the present invention provides novel oral compositions comprising SIP modulators or agonists. In an embodiment, it addresses the problem of reducing the negative chronotropic effect of such compounds.
  • Embodiments of the invention are predicated at least in part on the provision of such a compound in a modified release formulation, thereby to reduce or eliminate the negative chronotropic effect.
  • the compounds to which the application relates are therefore SIP receptor modulators or agonists.
  • the compounds are as disclosed in WO 04/103306 and and US
  • A is COORs, OPO(OR 5 ) 2 , PO(OR 5 ) 2 , S0 2 OR 5 , POR 5 OR 5 or 1 H-tetrazol-5-yl, R 5 being H or an ester-forming group, e.g. C ⁇ alkyl, and in one implementation of the invention being H;
  • W is a bond, C 1-3 alkylene or C 2-3 alkenylene
  • Y is G 6 .i 0 aryl or C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, N0 2 , Ci -6 alkyl, C 1-6 alkoxy; halo-substituted Ci. 6 alkyl and halo-substituted
  • Z is chosen from:
  • R 6 is chosen from hydrogen and C -6 alkyl; and Ji and J 2 are independently methylene or a heteroatom chosen from S, O and NR 5 ; wherein R 5 is chosen from hydrogen and C h alky!; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, C 1-6 alkyl; or R 6 can be attached to a carbon atom of Y to form a 5-7 member ring;
  • Ri is C 6 -ioaryl or C 3 . 9 heteroaryl, optionally substituted by Ci -6 alkyl, Ce-ioaryl, C 6 . 10 arylCi. alkyl, C 3-9 heteroaryl, C 3 . 9 heteroarylCi. alkyl, C 3 . 8 cycloalkyl, C 3 . 8 cycloalkylC 1-4 alkyl,
  • any aryl, heteroaryl, cycloalkyi or -heterocycloalkyl of Ri may be substituted by 1 to 5 groups selected from halogen, d. 6 alkyl, d-ealkoxy and halo substituted-C 1-6 alkyl or -d- 6 alkoxy;
  • R 2 is H, C 1-6 alkyl, halo substituted C -6 alkyl, C 2 . 6 alkenyl or C 2 - 6 alkynyl; and each of R 3 or R 4 , independently, is H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy or halo substituted C 1-6 alkyl or d-ealkoxy; or a pharmacologically acceptable salt, solvate or hydrate thereof.
  • the designation "Ci. 6” means “having 1 , 2, 3, 4, 5 or 6 carbon atoms” and the designation “CW means “having 3, 4, 5, 6, 7 or 8 carbon atoms”.
  • the designation "C 1-4” means “having 1 , 2, 3 or 4 carbon atoms”.
  • the designation "C 3 - 9” means “having 3, 4, 5, 6, 7, 8 or 9 carbon atoms”.
  • the invention particularly, but not exclusively, involves compounds of formula A1 or A2 in which R 5 is H, e.g. 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-cyclohexyl-3-trifluoromethyl- benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid and pharmaceutically acceptable salts, e.g. hemifumarate salts.
  • the invention provides a pharmaceutical composition for oral administration which comprises an active pharmaceutical ingredient ("API") selected from SIP receptor modulators and agonists, for example the compounds of Formulae A1 and A2, wherein the composition is adapted to provide sustained release of the API.
  • the composition may increase Tmax or reduce Cmax, or both increase Tmax and reduce Cmax, as compared to an immediate release composition.
  • a sustained release composition as compared to an immediate release composition comprises one or more agents which act to prolong release of the API; for example, the API may be embedded in a matrix and/or surrounded by a_ membrane which, in either case, controls (reduces) the rate of diffusion of the API into the Gl tract.
  • membrane-control is osmotic pump systems in which a core comprises e.g.
  • the controlled release may be achieved using a multiparticulate system comprising a number of independent sub-units to release the active.
  • the composition comprises a hydrogel-former, for example a hydrogel- forming polymer.
  • the composition may comprise hydrogel-former in admixture with the API.
  • the hydrogel-forming polymer may be, or comprise, a cellulosic polymer, e.g. hypromellose.
  • compositions of the invention further have one, two or three of the following features which serve to enhance stability of the API when it is of formula A1 or A2:
  • the API is in the form of particles having a crystallinity of 80% or more • the API is in the form of particles having an X90 diameter of at least 8pm, e.g. at least 10pm.
  • a particular embodiment resides in a tablet having a compressed composition
  • a hydrogel-former in admixture with a compound mentioned herein, e.g. 1- ⁇ 4-[1-(4-cyclohexyl- 3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid and its pharmaceutically acceptable salts e.g. its hemifumarate salt as the API.
  • the hydrogel- former may be non-basic and in particular is hypromellose, e.g. a mixture of two or more hypromellose materials of different grades.
  • the compressed composition may consist of non-basic materials; the matrix may for example contain, in addition to the API and a hydrogel-former, a non-basic filler, e.g. lactose (particularly as the monohydrate), a non- basic lubricant, e.g. glyceryl behenate, and a non-basic glidant, e.g. colloidal silicon dioxide.
  • a non-basic filler e.g. lactose (particularly as the monohydrate)
  • a non- basic lubricant e.g. glyceryl behenate
  • a non-basic glidant e.g. colloidal silicon dioxide.
  • the API may be in the form of particles which have an X90 diameter of from 10 pm to 200 pm and/or which are at least 80% crystalline.
  • the compressed mixture may include a desiccant, as which colloidal silicon dioxide also functions.
  • the compressed composition consists of non-basic materials in the form of particles which have an X90 diameter of from 10 pm to 200 pm and/or which are at least 80% crystalline.
  • compositions of the present invention may be used to treat autoimmune diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis and multiple sclerosis, amongst many others, e.g. as disclosed in ' WO2004/103306 and US 2009/0036423 for example in paragraphs [0041]-[0042] of US 2009/0036423.
  • autoimmune diseases e.g. rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis and multiple sclerosis
  • compositions of the present invention may be used to treat peripheral neurapathies, for example motor neuron disease, Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy with conduction block (M N), or paraproteinaemic demyelinating peripheral neuropathy (PDN).
  • the compositions of the invention are used to treat multiple sclerosis.
  • the invention therefore includes a method for treating a subject in need thereof, e.g. having or suspected of having one of the aforesaid diseases, e.g. multiple sclerosis, comprising administering to the patient a composition of the invention.
  • the composition is desirably administered in an effective amount.
  • Figure 1 shows simulated plasma levels of compound NVS-A following single oral administration of a 4 mg immediate release (“IR”) and modified release (F10 and F16) tablet.
  • IR immediate release
  • F10 and F16 modified release
  • Figure 2 is a plot of heart rate reduction following administration of a 4 mg immediate release and expected reduction following administration of modified release tablets compared to placebo (PBO). Profiles are shown for two modified release tablets, namely a tablet with a 10 hour release profile (designated F10). and a tablet with a 16 hour release profile (designated F16).
  • Figure 3 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 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl- benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3- carboxylic acid.
  • Figure 4 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-cyclohexyl-3-trifluoromethyl- benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3- carboxylic acid.
  • Figure 5 is a line graph which compares the sum of degradation products of four different compositions, each comprising 0.25 mg (equivalent base weight) of the hemifumarate salt of 1 - ⁇ 4-[1 -(4-cyclohexyl-3-trif luoromethyl- benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3- carboxylic acid mixed with a lubricant.
  • treat includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be afflicted 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) inhibiting the state, disorder or condition (e.g., 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 symptom thereof); and/or (3) relieving the condition (i.e., causing regression 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 medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.
  • Effective amount means an amount of an API or pharmaceutical composition sufficient to result in the desired 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.
  • Cmax means the peak concentration of the drug in the plasma.
  • Tmax means the time from administration to reach Cmax.
  • the invention relates to oral pharmaceutical compositions comprising as an API an SIP receptor modulator or agonist, e.g. 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 (equivalent base weight) or less of the API, e.g. 7.5mg or less of the API, for example 5mg or less of the API.
  • Some solid phase dosage units, e.g. tablets contain 0.1 mg (equivalent base weight) or more API, e.g. 0.2mg or more of the API, for example 0.25mg or more API.
  • dosage units e.g.
  • tablets which contain from 0.1 mg to 10mg of the API (equivalent base weight), e.g. 0.2mg to 7.5mg of the API; particular dosage units, e.g. tablets, contain from 0.25mg to 5mg of the API, for example 2.5mg to 5mg of the API.
  • the dosage units e.g. tablets
  • the dosage units contain no more than 4mg of the API (equivalent base weight), e.g. from 0.2mg or 0.25mg to 4mg of the API. Some dosage units contain from 2mg or 2.5mg to 4mg of the API. In one embodiment, the dosage units (e.g. tablets) contain 4mg of the API (equivalent base weight).
  • the compound is of formula A1. It will be understood that this embodiment, like all embodiments mentioned herein, is applicable across the entire scope of the disclosure, including to ail other embodiments disclosed herein, including those disclosed in the following paragraphs.
  • R 5 is H.
  • A is COOR 5 , and in particular is COOH.
  • Z is
  • A-Z is
  • Y is phenyl optionally substituted by 1 , 2 or 3 radicals selected from halogen, N0 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted Ci -6 alkyl and halo-substituted
  • Y is phenyl substituted by a single said radical, e.g. by a single C 1-6 alkyl radical.
  • C 1-6 means "having 1 , 2, 3, 4, 5 or 6 carbon atoms" and an exemplary d- ⁇ alkyl radical is ethyl.
  • A-Z-C( R3)-Y- is
  • R 7 is H, halogen, Nd 2 , C -6 alkyl, d-ealkoxy; halo-substituted d-ealkyl and halo- substituted d-ealkoxy, and in particular is d-ealkyl e.g. ethyl.
  • W is d, d or d 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 d, d or C 3 alkylene, particularly methylene), the compound may be of the formula A1 and/or Y may be an optionally substituted phenyl group as previously described herein and in articular where A-Z-C(R 4 )(R 3 )-Y- may be
  • Ri is phenyl substituted by phenyl or by C 3 -C 8 cycloalkyl, e.g. by cyclohexyl, wherein each phenyl and cyclohexyl are each independently optionally substituted by 1 or 2 substituents selected from halogen, d. 6 alkyl, d -6 alkoxy and halo substituted-d -6 alkyl or -d. 6 alkoxy.
  • Ri may therefore be phenyl substituted by -d cycloalkyl, each optionally substituted as just mentioned; in one sub-embodiment, phenyl of RT is substituted by a single substituent, e.g. fluoro or in particular trifluoromethyl, and cycloalkyl of Ri is unsubstituted cyclohexyl.
  • phenyl is 1 ,4-substituted by W and cycloalkyl (e.g. unsubstituted cyclohexyl).
  • the designation "C 3 -C 8" means having 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. 5 or 6 carbon atoms.
  • the compound is of formula A1 ;
  • W is C 1t C 2 or C 3 alkylene;
  • Y is a phenyl group optionally substituted by 1 , 2 or 3 radicals selected from halogen, N0 2 , C 1-6 alkyl, 6 alkoxy; halo-substituted d -6 alkyl and halo-substituted Ci. 6 alkoxy; and is phenyl substituted by C 3 -C 8 cycloalkyi, wherein phenyl and cyclohexyl are each independently optionally substituted by 1 or 2 substituents selected from halogen, C h alky!, Ci. 6 alkoxy and halo substituted-C 1-6 alkyl or -C ealkoxy.
  • WO 20 0/072703 teaches that SIP receptor agonists have a negative chronotropic side effect.
  • the invention is predicated at least in part by an insight that the negative
  • chronotropic effect may be ameliorated without rendering the drug therapeutically useless by administering the drug in sustained release form.
  • the invention provides a pharmaceutical composition for oral administration which comprises an active pharmaceutical ingredient ("API") selected from SIP receptor modulators and agonists, wherein the composition is adapted to provide sustained release of the API.
  • API active pharmaceutical ingredient
  • the API is selected from the compounds of Formulae A1 and A2.
  • the invention in some embodiments is in part predicated on a finding that an active compound as disclosed above, namely the hemifumarate salt of 1- ⁇ 4-[1-(4-cyclohexyl-3- trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, has poor stability in certain settings and that stability of the compound in a pharmaceutical composition may be improved by adopting one, two or three of the following measures:
  • the composition is substantially dry, e.g. is made of substantially moisture- free constitutents, and is provided with a moisture-protective layer as a barrier to ingress of water and/or includes a desiccant.
  • the composition for example in the form of a tablet, comprises a desiccant.
  • the composition for example in the form of a tablet, is provided with a moisture-protective layer.
  • the composition for example in the form of a tablet, comprises a desiccant and is provided with a moisture-protective layer.
  • hemifumarate salt 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 compound as an active pharmaceutical ingredient (API) of a composition.
  • API active pharmaceutical ingredient
  • API is formula A1 or A2
  • embodiments of the invention lie in sustained release compositions, for example capsules or tablets, particularly tablets, having one the following characteristics (1) to (6):
  • the API is not exposed to basic compounds, e.g. basic compounds are excluded from the composition, and the API is in the form of particles having a crystallinity of 80% or more;
  • the API is not exposed to basic compounds, e.g. basic compounds are excluded from the composition, and the API is in the form of particles having an X90 diameter of at least 8 ⁇ e.g. at least 10pm;
  • the API is in the form of particles having an X90 diameter of at least 8pm e.g. at least 10pm and a crystallinity of 80% or more;
  • the API is not exposed to basic compounds, e.g. basic compounds are excluded from the composition, and the API is in the form of particles having an X90 diameter of at least 8 ⁇ e.g. at least 10pm and a crystallinity of 80% or more; (5) any of (1), (2), (3) and (4) in combination with inclusion of a desiccant in the composition;
  • compositions of the invention comprise an API selected from the compounds of Formulae A1 and A2, wherein the API is not exposed to a basic compound.
  • compositions of the invention comprise an API selected from the compounds of Formulae A1 and A2, wherein the API is in the form of particles having an X90 diameter of at least 8pm and optionally of at least 1 ⁇ .
  • compositions of the invention comprise an API selected from the compounds of Formulae A1 and A2, wherein the API is in the form of particles having a crystallinity of 80% or more.
  • compositions comprise an API selected from the compounds of Formulae Aland A2, wherein the API is in the form of particles having an X90 diameter of at least 8pm and optionally of at least 10pm and a crystallinity of 80% or more.
  • a further embodiment resides in compositions of the invention which comprise an API selected from the compounds of Formulae A1 and A2, 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.
  • the composition is free of basic compounds.
  • compositions of the invention which comprise an API selected from the compounds of Formulae A1 and A2, wherein the API is in the form of particles which have a crystallinity of 80% or more and which are not exposed to a basic compound.
  • compositions of the invention comprise an active pharmaceutical ingredient ("API") selected from the compounds of Formulae A1 and A2, and one or more pharmaceutically acceptable excipients, wherein the API is in the form of particles which have have an X90 diameter of at least 10pm and a crystallinity of 80% or more and which are not exposed to a basic compound.
  • API active pharmaceutical ingredient
  • compositions of the invention comprise one or more pharmaceutically acceptable excipients, as well as an API.
  • the excipient(s) will include a sustained release component, e.g. polymer.
  • the invention is not limited as to the manner in which sustained release is achieved.
  • the sustained release is pH-independent.
  • a polymer may be included in the formulation which acts to control the release of the API, e.g. in a pH- independent manner.
  • a polymer for example a hydrogel-forming polymer, is in admixture with the API to form a matrix, or it is comprised in a coating, or it both forms a matrix and is comprised in a coating.
  • the compositions of the invention comprise a hydrogel-former, for example a single polymer or a combination of two or more polymers.
  • the hydrogel-former may be in admixture with the API, or in a coating, or both in admixture with the API and in a coating.
  • the hydrogel former comprises, or is, at least one hypromellose.
  • the API is a compound of formula A1 or A2 and that sustained release agent is non-basic, for example a non-basic hydrogel-former such as, e.g., hypromellose.
  • Some compositions of the invention comprise a combination of two or more different hypromellose materials, for example having different viscosities, whereby a desired balance of properties may be achieved.
  • hydrophobic polymers for example ethyl cellulose or a methacrylic acid polymer, or a combination thereof.
  • Such polymers may be comprised in a coating or may be included in admixture with the API (i.e. may be used as a matrix-former), or may be present both in a coating and in admixture with the API.
  • materials which may be included in the composition to provide sustained release are insoluble erodible materials, for example a wax or a hydrogenated vegetable oil, or a combination thereof.
  • insoluble erodible materials for example a wax or a hydrogenated vegetable oil, or a combination thereof.
  • Such materials may be comprised in a coating or may be included in admixture with the API (i.e. may be used as a matrix-former), or may be present both in a coating and in admixture with the API.
  • hydrophilic polymers other than hypromellose for example a non-basic poly(ethylene oxide) or sodium alginate, or a combination thereof.
  • Such materials may be comprised in a coating or may be included in admixture with the API (i.e. may be used as a matrix-former), or may be present both in a coating and in admixture with the API.
  • a basic material e.g. sodium alginate, it is in the case of APIs of formula A1 or A2 preferably confined to a coating and not used in admixture with the API.
  • an osmotic pump system may be used to obtain sustained release.
  • compositions comprising an API of Formula A1 or A2
  • the API should not be in contact with an basic sustained release agent.
  • basic matrix materials are desirably avoided in relation to such APIs.
  • the sustained release composition provides a zero order (linear) release profile, for example for a period of at least 5 hours, e.g. at least 10 hours and optionally for 16 hours or more.
  • a zero order (linear) release profile provides the optimal profile to minimise undesirable cardiac side effects e.g. the negative chronotropic effect and or AV blocks sometimes associated with administration of some S1P receptor modulators.
  • Suitable compositions may be determined empirically.
  • Linear release compositions may conveniently be made by using a hydrogel-former as a matrix, for example a single grade of hypromellose or a combination of different grades of hypromellose may be used to achieve linear release, e.g. in the compositions described in the examples of this specification.
  • the invention includes compositions comprising an insoluble, erodible matirx material such as a wax or cellulosic polymer.
  • the invention includes embodiments which have the effect of increasing Tmax.
  • the invention includes embodiments which have the effect of reducing Cmax.
  • the invention includes embodiments which have the effect of increasing Tmax and reducing Cmax. It is contemplated that the aforementioned compositions comprising a hypromellose matrix (e.g. a single hypromellose material or a combination thereof) will both increase Tniax and reduce Cmax but the invention is not limited to such hypromellose matrices.
  • Sustained release agents which reduce Cmax, increase Tmax or both may be chosen empirically.
  • APIs of formula A1 or A2 have been found to have poor stability in admixture with the following basic compounds, which should therefore be avoided from being combined with such APIs in the tableting composition: sodium starch glycolate (sold under the trade mark . Primojel®), sodium lauryl sulfate, magnesium stearate, calcium stearate, calcium carbonate, calcium sulfate, sodium stearyl fumarate and sodium bicarbonate.
  • the above-mentioned APIs also have poor stability in admixture with gelatine, and this is preferably not included with these APIs.
  • any such API is in a mixture of materials which is free of basic compounds.
  • the composition is free of basic compounds (provided that the compound of formula A1 or A2 may have its moiety A (e.g. -COOH) in acid or salt form).
  • the invention includes, for . example, the provision of two- or multi-part compositions of which one part incorporates a compound of formula A1 or A2 but is free of any basic compound (provided that the compound of formula A1 or A2 may have its moiety A (e.g.
  • a basic compound may be an impurity which it is not possible or practicable to remove entirely or to an undetectable level.
  • moiety A is not in the form of a salt but 5 is present as H or an ester- forming group. R 5 particularly is present as H (i.e. moiety A is in its acid form and not as a salt).
  • the pharmaceutical composition comprises a tablet comprising a compressed composition which consists of a compound of formula A1 or A2 in admixture with a non-basic sustained release agent (e.g. a hydrogel former) and one or more other non-basic compounds.
  • a non-basic sustained release agent e.g. a hydrogel former
  • the one or more other non-basic compounds may comprise or consist of non-basic excipients, e.g. selected from: binders, glidants, lubricants, fillers, diluents, and sorbents.
  • the 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 APIs in addition to one or more APIs of formula A1 or A2.
  • the tablet 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 W01996/001874, included herein by reference for all purposes, and comprises polyvinyl alcohol, soya lecithin, and optionally a flow aid, a colorant, and/or a suspending agent.
  • the composition includes a desiccant, e.g. colloidal silica.
  • the pharmaceutical composition comprises a tablet comprising a compressed composition which consists of a compound of formula A1 or A2 in admixture with hypromellose and further excipients selected from lactose (e.g. as lactose
  • hypromellose is considered to act as a sustained release agent, lactose as a filler, microcrystalline cellulose as a binder, colloidal silicon dioxide as a glidant and the remaining materials as lubricants; in embodiments, only a single such lubricant is included in the composition, e.g. glyceryl behenate.
  • Colloidal silicon dioxide acts also as a desiccant.
  • An embodiment of the invention therefore comprises a tablet which comprises a compressed phase which consists of a compound of formula A1 or A2 in admixture with lactose (e.g. as lactose monohydrate), microcrystalline cellulose, colloidal silicon dioxide, hypromellose and a lubricant selected from stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol (e.g. polyethylene glycol 4000-6000), glyceryl palmitostearate and glyceryl behenate, and combinations of the aforesaid lubricant compounds.
  • lactose e.g. as lactose monohydrate
  • microcrystalline cellulose microcrystalline cellulose
  • colloidal silicon dioxide hypromellose
  • a lubricant selected from stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol (e.g. polyethylene glycol 4000-6000), glyceryl palmitostearate and glyceryl behenate, and combinations of the aforesaid
  • lactose monohydrate microcrystalline cellulose
  • colloidal silicon dioxide hypromellose
  • a lubricant selected from hydrogenated vegetable oil, mineral oil, polyethylene glycol (e.g. polyethylene glycol 4000-6000), glyceryl palmitostearate and glyceryl behenate, and combinations of the aforesaid lubricant compounds.
  • a single lubricant is present in the solid phase mixture, particularly glyceryl behenate.
  • an embodiment of the invention is in part predicated on a finding that the stability in a solid phase composition, particularly a tablet, of an active compound as disclosed above, namely 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2- ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, and pharmaceutically acceptable salts, e.g.
  • hemifumarate salt 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 uniformity requirement.
  • Content uniformity is influenced by the particle size of the drug substances.
  • Median particle size is denoted by X m , where m is a percentage of the particle size distribution.
  • the invention therefore provides a solid phase sustained release formulation, particularly a tablet, comprising a compound of formula A1 or A2 in a relatively large particle size, e.g. 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 further optionally of 150pm or more.
  • the particle size (X90 diameter ) may be up to 300pm, e.g. up to 250pm, and optionally up to 200pm (e.g.
  • the X90 diameter is of from 10pm to 300pm, e.g. 10pm to 250pm or 10pm to 200pm. Also included are embodiments in which the particle size (X90 diameter) is from 25pm to 300pm, e.g. 25pm to 250pm or 25pm to 200pm. Further included are embodiments in which the X90 diameter is from 100pm to 300pm, e.g. 100pm to 250pm or 100pm to 200pm. In a particular embodiment, the X90 particle diameter is at least 10 pm and is less than 191 pm, e.g. less than 180pm, less than 170 pm, less than 160 pm, less than 150 pm, less than 140 pm or less than 130 pm, e.g.
  • the X90 particle diameter is at least 25 pm and is less than 191 pm, e.g. less than 180pm, less than 170 pm, less than 160 pm, less than 150 pm, less than 140 pm or less than 130 pm, e.g. no more than 125 pm, such as no more than 121 pm.
  • the X90 particle diameter is at least 10 pm or 25 pm but no more than 100pm, e.g. 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.
  • the X90 particle diameter is from 121 pm to 191 m. In another embodiment, the X90 particle diameter is from 1 1 pm to 29pm.
  • An embodiment of the invention is in part predicated on a finding that, in the case of an API of formula A1 or A2, API 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 sustained release pharmaceutical compositions of the present invention may fulfil, 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 particle size which enables the requirement to be met cannot be stipulated because the maximum possible particles size varies with the drug content of the dosage unit.
  • API particles having an X90 diameter of 121 pm complied with the harmonised content uniformity requirement whereas API particles having an X90 diameter of 191pm failed to comply.
  • API particles having an X90 diameter of up to 191 pm complied with, the harmonised content uniformity requirement.
  • a maximum particle size which enables any particular tablet composition to meet the harmonised content uniformity requirement may be determined empirircally.
  • the particle size distribution (by volume) may be measured using a laser diffraction sizing instrument, for example the Sympatec Helos device (available from Sympactec GmbH, Germany) using the Cuvette dispersion device.
  • the X 90 diameter is the spherical diameter corresponding to the X 90 volume.
  • a stock dispersion may be prepared by mixing the drug substance with a dispersing aid (e.g Octastat 5000 (Octel 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 cumulative volume size curve by the software of the Sympatec instrument. X90 mean 90% of the particle size population is below the specified value in volume.
  • a solid phase sustained release pharmaceutical composition in unit dosage form particularly a tablet, which comprises one or more pharmaceutically acceptable excipients, in particular non-basic excipients, and an API as described herein and which complies with the US Pharmacopeia, European Pharmacopeia and Japanese Pharmacopeia harmonised content uniformity requirements as in force on 1 January 2011 ;
  • a solid phase sustained release pharmaceutical composition in unit dosage form particularly a tablet, which comprises one or more pharmaceutically acceptable excipients, in particular non-basic excipients, and an API as described herein in an amount of from 4 mg to 6mg API, the API being as particles have an X90 diameter of at least 100pm but no more than 300pm, e.g. from 100pm to 250 ⁇ , from 100pm to 200pm, from 100 ⁇ to 190 ⁇ , from 100pm to 180pm, from 100pm to 170pm; from 100 ⁇ to 160pm or from 100pm to 150pm;
  • a solid phase sustained release pharmaceutical composition in unit dosage form particularly a tablet, which comprises one or more pharmaceutically acceptable and preferably non-basic excipients, including a sustained release agent, and an API as described herein in an amount of from from 0.2 mg to 1 mg API, the API being as particles have an X90 diameter of at least 10 ⁇ but no more than 100pm, e.g. 10pm to 90 ⁇ , 10pm to 80pm, 10 ⁇ ⁇ to 70pm, 10pm to 60 ⁇ , 10pm to 50pm, 10pm to 40pm or 10 ⁇ to 30pm.
  • An aspect of the invention resides in compounds of formula A1 or A2 when in particulate form having an X90 diameter as disclosed herein, as well as products or compositions of matter comprising such particulate compounds. CrystalHnity
  • the invention is in part also predicated on a finding that the stability in a solid phase formulation, particularly a tablet, of an active compound as disclosed above, namely 1- ⁇ 4-[1- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, may be enhanced by the active compound being in particles of relatively high crystallinity, e.g. a crystallinity of 80% or more, for example 85% or more and optionally of 90% or more.
  • 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2- ethyl-benzyl ⁇ -azetidine-3-carboxylic 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 compound as an active pharmaceutical ingredient (API) of a sustained release composition.
  • the invention therefore provides a sustained release solid phase formulation, 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.
  • a aspect of the invention resides in compounds of formula 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 crystallinity.
  • a crystallinity of 80% or more may be attained by a compound of formula A1 or A2 being as particles having an X90 diameter of 10pm or more and particularly 11 pm or more, for example 20pm or 25pm or more, optionally of 100pm or more and further optionally of 150pm or more.
  • the X90 diameter may be as previously described herein Under the heading "Particle Size".
  • Crystallinity may be measured using X-ray powder diffraction (XRPD), for example using a Bruker D8 device.
  • XRPD X-ray powder diffraction
  • solid phase compositions e.g. tablets
  • compositions of the invention may.suitably 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 optionally applying a film coating, for example a sustained release film, to the compressed tablet.
  • a film coating for example a sustained release film
  • API particles can be prepared by suitable milling techniques, e.g. those well known in the art such as, for example, pin-milling, wet-jet milling and wet-ball milling.
  • the coarse crystals may be obtained using any suitable methodolgy.
  • a pharmaceutical composition for oral administration which comprises an active pharmaceutical ingredient (“API") selected from SIP receptor modulators and agonists, wherein the composition is adapted to provide sustained release of the API.
  • API active pharmaceutical ingredient
  • composition of numbered paragraph 1 which increases Tmax as compared to an immediate release composition.
  • composition of numbered paragraph 1 or 2 which reduces Cmax as compared to an immediate release composition.
  • composition of any preceding numbered paragraph which has a zero order release profile for a period of at least 5 hours.
  • composition of numbered paragraphs which has a zero order release profile for a period of at least 10 hours and optionally for 16 hours or more.
  • composition of any previous numbered paragraph which comprises a polymer which controls the release of the API in a pH-independent manner.
  • composition of any previous numbered paragraph which comprises a hydrogel- former.
  • composition of numbered paragraph 7 or 8 wherein the hydrogel-former comprises, or is, at least one hypromeliose.
  • composition of numbered paragraph 9 wherein the hydrogel-former is hypromeliose having an apparent viscosity of 80-120 mPa.s or a mixture of equal parts by weight of hypromeliose having an apparent viscosity of 80-120 mPa.s and of hypromeliose having an apparent viscosity of 75000-140000 mPa.s.
  • composition of any preceding numbered paragraph which is a tablet. . 2.
  • A is COORs, OPO(OR 5 ) 2 , PO(OR 5 ) 2 , S0 2 OR 5l POR 5 OR 5 or 1 /-tetrazol-5-yl, R 5 being H or an ester-forming group;
  • W is a bond, Ci- 3 alkylene or C 2 - 3 alkenylene
  • Y is C 6 .i 0 aryl or C 3 - 9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, N0 2 , C ⁇ alkyl, C 1-6 alkoxy; halo-substituted C -6 alkyl and halo-substituted
  • Z is chosen from:
  • R 6 is chosen from hydrogen and C h alky!; and and J 2 are independently methylene or a heteroatom chosen from S, O and NR 5 ; wherein R 5 is chosen from hydrogen and C ⁇ alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, C 1-6 alkyl; or R 6 can be attached to a carbon atom of Y to form a 5-7 member rin rylC 1 . 4 alkyl, , cycloalkyl
  • heterocycloalkyl of may be substituted by 1 to 5 groups selected from halogen, d. 6 alkyl, C ⁇ alkoxy and halo substituted-C ⁇ alkyl or -d-ealkoxy;
  • R 2 is H, d-ealkyl, Halo substituted C h alky!, C 2 . 6 alkenyl or C 2-6 alkynyl; and each of R 3 or R 4 , independently, is H, halogen, OH, C 1-6 alkyl, d-ealkoxy or halo substituted C 1-6 alkyl or C 1-6 alkoxy.
  • composition of numbered paragraph 2 or 13 wherein the compound is of formula A1. 15. A composition of numbered paragraph 14 wherein:
  • W is CL C 2 or C 3 alkylene
  • Y is a phenyl group optionally substituted by 1 , 2 or 3 radicals selected from halogen, N0 2 , C ⁇ alkyl, Ci. 6 alkoxy; halo-substituted C -6 alkyl and halo-substituted C -6 alkoxy; and
  • Ri is phenyl substituted by C 3 -C 8 cycloalkyl, wherein phenyl and yclohexyl are each independently optionally substituted by 1 or 2 substituents selected from halogen, d. 6 alkyl, C 1-6 alkoxy and halo substituted-Ci. 6 alkyl or -C 1-6 alkoxy.
  • composition of any preceding numbered paragraph wherein the API is selected from the compounds as defined in any of numbered paragraphs 12 to 17 and is in the form of particles having an X90 diameter of at least 8pm.
  • composition of numbered paragraph 21 wherein the particles have an X90 diamater of at least 10pm but no more than 100pm.
  • composition of numbered paragraph 21 wherein the particles have an X90 diameter of at least 100pm but no more than 250pm.
  • composition of any of numbered paragraphs 20 to 23 which is in unit dosage form and complies with the US Pharmacopeia, European Pharmacopeia and Japanese
  • a composition of numbered paragraph 24 which is in the form of a tablet containing from 4 mg to . 6mg API (equivalent free base weight) and particles have an X90 diameter of at least 100pm but no more than 200pm.
  • a composition of numbered paragraph 24 which is in the form of a tablet containing . from 0.2 mg to 1 mg API (equivalent free base weight) and particles have an X90 diameter of at least 10pm but no more than 50pm.
  • composition of any preceding numbered paragraph wherein the API is selected from the compounds as defined in any of claims 12 to 17 and has a crystallinity of 80% or more.
  • a tablet comprising a compressed mixture consisting of 1- ⁇ 4-[1-(4-cyclohexyl-3- trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid or its hemifumarate salt and one or more non-basic excipients including a hydrogel-former, the 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3- carboxylic acid or hemifumarate salt being in the form of particles having an X90 diameter of from 10 pm to 200 pm.
  • NVS-A The hemifumarate salt form of compound 1- ⁇ 4-[1-(4-cyclohexyl-3-trif
  • a clinical ascending dose study is undertaken with compound NVS-A.
  • a decrease in heart rate was demonstrated at single doses > 0.3 mg .
  • the maximum bradycardia effect approximately occured 3 hours post dose, the heart rate then returned to its initial rhythm 10 hours post dose.
  • the maximum decrease in heart rate was observed on the first day of treatment; the bradycardia then tended to disappear after 4 days which seems to indicate a "tolerance build up”.
  • GastroplusTM data were used to optimise the pharmacokinetic profile so that a reduction in heart rate could be achieved.
  • the PK profile obtained with the 4 mg immediate release tablet is presented.
  • the plasma concentration peaked between 3 to 6 hours post dose. From the GastroplusTM simulation, it was recommended to generate a release profile shifting the Tmax to around 10 hours for a first modified release prototype and at least 16 hours for a second one.
  • Hydrogel matrix tablets having a linear release profile over, respectively, 10 hours and at least 16 hours were made by direct compression of the dry blend in accordance with the compositions given in Table 1 :
  • Table 1 Composition of the NVS-A modified release tablets
  • Hypromellose/ Hypromellose 10.200 Controlled Ph.Eur./USP (Type 2208) 2 . Release
  • Hypromellose/Hydroxypropylmethy!-cellulose (HPMC 2910), (E464) Ph.Eur./USP
  • Titanium Dioxide (E171 , C.I. 77891 ) Ph.Eur./USP
  • Example 1 discloses the stability of compound NVS-A in the presence of various compounds. Mixtures of NVS-A with various compounds were exposed in a sealed vial to conditions of 50°C temperature and 75% relative humidity for 4 weeks. After 4 weeks, the degradation of of NVS-A and sum of degradation products was assayed.
  • 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- acetonitrile containing 0.2% (v/v) formic acid and 10% (v/v) Triethylamine.
  • NVS-A film coated tablet comprising micronised drug substance, lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate.
  • a moisture protective Opadry® AMB film coating was applied. Tablet, strengths from 0.25 mg to 5 mg (equivalent free base weight) were produced (see Table 4 below). ]
  • Table 4 Composition of the immediate release 0.25 and 5 mg tablet containing magnesium stearate as lubricant.
  • NVS-A base corresponds to 0.25 mg (e.g. 0.294% w/w)
  • 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 tablet.the stability data did not fulfill the stability guidance from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
  • the X 90 particle size distribution (by volume) was measured using a laser diffraction sizing instrument [the Sympatec Helos device (available from Sympactec GmbH, Germany) using the Cuvette dispersion device.
  • a stock dispersion was prepared by mixing the drug substance with a dispersing aid (Octastat 5000 (Octel corp)) using a vortex until a smooth and homogeneous paste was formed.
  • the paste was then diluted and mixed to a final volume of 3 to 6 ml using white spirit.
  • the optical concentration of the final solution were kept below 5%.
  • the percentage values were calculated from the mean cumulative volume size curve by the software of the Sympatec instrument. Additional confirmatory information on particle size was obtained using SEM (scanning electron microscopy).
  • the finer API material (X 90 ⁇ 10pm (4 and 7 pm) was obtained by micronisation using a jet mill [ Hosokawa Alpine AFG100] using a pressure in the range from 2 to 5 bars.
  • the material with X 90 at 1 1 , 29 pm and 121 ⁇ was obtained by milling in this case with a pin mill with the relative tin speed being adjusted from 1 15, to 75 to 40 m/sec respectively.
  • the coarser material with X 90 pm of 191 urn was obtained by sieving on a 457um sieve.
  • the drug substance particle sizes considered showed reduced impact on the mean content uniformity value and its variability for the 5 mg tablet:
  • API drug particles were obtained and measured as in Example 6.
  • the following example compares the sum of degradation products of four different compositions, each comprising 0.25 mg (equivalent free base weight) of NVS-A mixed with a lubricant.
  • the lubricants and the particle sizes of each composition are as follows: The table below summarises the difference in composition between the tablets made with magnesium stearate and glyceryl behenate as lubricant. It should be noted that the tablet made with glyceryl behenate and with the different drug substance particle size were not coated with the moisture protective film coated opadry AMB in order to better demonstrate the stability benefit. API drug particles were obtained and measured as in Example 6.
  • Table 5 Composition of the immediate release 0.25 mg tablet (equivalent free base weight) containing magnesium stearate and glyceryl behenate as lubricant.
  • NVS-A base corresponds to 0.25 mg (e.g. 0.294% w/w)
  • Composition 1 exhibited around 16% degradation product after 3 months of storage.
  • composition 2 exhibited around 4% degradation product after 3 months of storage.
  • composition 3 exhibited around 2% degradation product after 3 months of storage.
  • composition 4 exhibited around 1 % degradation product after 3 months of storage.

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Abstract

La présente invention concerne une composition pharmaceutique à administration orale comprenant un principe actif pharmaceutique (PA) choisi parmi des agonistes et des modulateurs des récepteurs SIP, cette composition permettant d'assurer une libération prolongée du PA.
PCT/IN2011/000020 2011-01-10 2011-01-10 Formulations à libération modifiée comprenant des modulateurs des récepteurs sip Ceased WO2012095853A1 (fr)

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AU2015246038C1 (en) * 2014-04-10 2018-05-31 Novartis Ag Immunosuppressant formulation
EP3831378A1 (fr) 2014-04-10 2021-06-09 Novartis AG Régime posologique de siponimod à libération immédiate pour le traitement des maladies auto-immunes
KR20160144366A (ko) * 2014-04-10 2016-12-16 노파르티스 아게 면역억제제 제제
CN106456552A (zh) * 2014-04-10 2017-02-22 诺华股份有限公司 S1p调节剂的立即释放剂量方案
JP2017510602A (ja) * 2014-04-10 2017-04-13 ノバルティス アーゲー 免疫抑制製剤
JP2017510607A (ja) * 2014-04-10 2017-04-13 ノバルティス アーゲー Ｓ１ｐ調節剤即時放出投与レジメン
CN106163502A (zh) * 2014-04-10 2016-11-23 诺华股份有限公司 免疫抑制剂配方
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CN106163502B (zh) * 2014-04-10 2020-12-01 诺华股份有限公司 免疫抑制剂配方
WO2015155709A1 (fr) 2014-04-10 2015-10-15 Novartis Ag Régime posologique de modulateur s1p à libération immédiate
EP4074312A1 (fr) 2014-04-10 2022-10-19 Novartis AG Régime posologique à libération immédiate de modulateurs s1p pour le traitement de maladies auto-immunes
KR102466348B1 (ko) 2014-04-10 2022-11-10 노파르티스 아게 면역억제제 제제
WO2015155711A1 (fr) * 2014-04-10 2015-10-15 Novartis Ag Formulation d'immunosuppresseur
US12049446B2 (en) 2017-03-09 2024-07-30 Novartis Ag Solid forms comprising an oxime ether compound and a coformer, compositions and methods of use thereof
US11629124B2 (en) 2017-03-09 2023-04-18 Novartis Ag Solid forms comprising an oxime ether compound, compositions and methods of use thereof
EP4321153A4 (fr) * 2021-04-14 2024-10-09 Lg Chem, Ltd. Composition pharmaceutique comprenant un agoniste du récepteur de la sphingosine-1-phosphate ayant une granulométrie contrôlée

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