US20130273161A1 - Immunosuppressant formulations - Google Patents

Immunosuppressant formulations Download PDF

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US20130273161A1
US20130273161A1 US13/917,730 US201313917730A US2013273161A1 US 20130273161 A1 US20130273161 A1 US 20130273161A1 US 201313917730 A US201313917730 A US 201313917730A US 2013273161 A1 US2013273161 A1 US 2013273161A1
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alkyl
api
ethyl
substituted
tablet
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Philippe Michel Rene Bouillot
Emeric Reynaud
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Priority to US17/230,175 priority patent/US20220064110A1/en
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, pharmaceutically acceptable salts, and related compounds.
  • S1P receptors belong to a family of closely related, lipid activated G- protein coupled receptors.
  • S1P1, S1P3, S1P2, S1P4, and S1P5 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 of diseases associated with S1P receptor mediated signal transduction.
  • the immunosuppressant compounds disclosed in WO2004/103306 affect the pathology and/or symptomology of these diseases by altering the activity of S1P receptors.
  • WO2004/103306 and US 2009/0036423 disclose 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid:
  • autoimmune diseases e.g. rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis and multiple sclerosis, amongst many others.
  • WO2004/103306 and US 2009/0036423 are incorporated herein by reference for all purposes, including by way of non-limiting example paragraphs [0041]-[0054], inclusive, of US 2009/0036423 and each example thereof.
  • WO2010/020610 discloses use of S1P 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 (CIDP), multifocal motor neuropathy with conduction block (MMN), and paraproteinaemic demyelinating peripheral neuropathy (PDN).
  • GBS Guillain-Barre syndrome
  • CIDP 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 S1P receptor agonist, propylene glycol and optionally glycerin, which concentrate is described as being stable for extended periods of time.
  • One compound mentioned as an S1P 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 S1P 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.
  • S1P 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 S1P modulator mentioned is 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid.
  • WO2010/072703 discloses a dosage regimen of an S1P receptor modulator for the treatment of patients suffering from an autoimmune disease, for example multiple sclerosis.
  • the dosage regimen comprises administering a lower dosage of an S1P 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 S1P receptor modulator.
  • One S1P modulator mentioned is 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid.
  • the present invention is predicated at least in part on a finding that, in relation to active pharmaceutical ingredients described later in this specification, pharmaceutical compositions having particular excipients are associated with reduced degradation of the active pharmaceutical ingredient as compared to alternative compositions of the same active pharmaceutical ingredient.
  • the invention is also predicated at least in part by a finding that provision of the active pharmaceutical ingredient as particles of relatively large size can improve stability whilst maintaining an adequately homogeneous content uniformity.
  • the compounds to which the application relates are compounds as disclosed in WO 04/103306 and US 2009/0036423, in particular compounds of formula A1 or A2:
  • A is COOR 5 , OPO(OR 5 ) 2 , PO(OR 5 ) 2 , SO 2 OR 5 , POR 5 OR 5 or 1H-tetrazol-5-yl, R 5 being H or an ester-forming group, e.g. C 1-6 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 C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, NO 2 , C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy;
  • Z is chosen from:
  • R 6 is chosen from hydrogen and C 1-6 alkyl; and J 1 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 1-6 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 ring;
  • R 1 is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1 may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or -C 1-6 alkoxy;
  • R 2 is H, C 1-6 alkyl, halo substituted C 1-6 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 C 1-6 alkoxy; or a pharmacologically acceptable salt, solvate or hydrate thereof.
  • C 1-6 means “having 1, 2, 3, 4, 5 or 6 carbon atoms” and the designation “C 3-8 ” means “having 3, 4, 5, 6, 7 or 8 carbon atoms”.
  • C 1-4 means “having 1, 2, 3 or 4 carbon atoms”.
  • 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 its pharmaceutically acceptable salts, e.g. its hemifumarate salt.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 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 not exposed to a basic compound.
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active pharmaceutical ingredient (“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 8 ⁇ m and optionally of at least 10 ⁇ m.
  • API active pharmaceutical ingredient
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active pharmaceutical ingredient (“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.
  • API active pharmaceutical ingredient
  • compositions comprising an active pharmaceutical ingredient (“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 8 ⁇ m and optionally of at least 10 ⁇ m and a crystallinity of 80% or more.
  • API active pharmaceutical ingredient
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising 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 an X90 diameter of at least 8 ⁇ m and optionally of at least 10 ⁇ m and which are not exposed to a basic compound.
  • the composition is free of basic compounds.
  • the invention includes pharmaceutical compositions comprising 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 a crystallinity of 80% or more and which are not exposed to a basic compound.
  • API active pharmaceutical ingredient
  • compositions comprising 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 an X90 diameter of at least 8 ⁇ m and optionally of at least 10 ⁇ m and a crystallinity of 80% or more and which are not exposed to a basic compound.
  • API active pharmaceutical ingredient
  • the composition is in particular a solid phase composition, for example a tablet or capsule, particularly a tablet.
  • the composition may be coated with a moisture barrier and an exemplary composition is a tablet coated with a moisture barrier.
  • the pharmaceutical composition may therefore comprise, or consist of, at least one API and one or more non-basic excipients.
  • the one or more non-basic excipients may be selected from binders, disintegrants, glidants, lubricants, fillers, diluents, and/or sorbents.
  • the tablets may comprise one or more tablet lubricants wherein the lubricants in the tablets are selected exclusively from stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol 4000-6000, glyceryl palmitostearate and glyceryl behenate.
  • the pharmaceutical composition comprises a non-basic sustained release agent, for example a non-basic hydrogel former, e.g. a hypromellose (hydroxypropylmethyl cellulose).
  • a non-basic hydrogel former e.g. a hypromellose (hydroxypropylmethyl cellulose).
  • a particular embodiment resides in a tablet comprising a compressed mixture which consists of 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof e.g. a hemifumarate salt and one or more non-basic excipients.
  • the 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-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 ⁇ m to 200 ⁇ m and/or which are at least 80% crystalline.
  • the compressed mixture may include a desiccant and/or be coated with a moisture barrier (e.g. both includes a desiccant and have a moisture barrier coating).
  • 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 (MMN), 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.
  • compositions of the invention for use in treating at least one of the aforesaid diseases, e.g. multiple sclerosis.
  • FIG. 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 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid.
  • FIG. 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-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid.
  • FIG. 3 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-trifluoromethyl-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.
  • 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 10 mg or less of the API (equivalent base weight), e.g. 7.5 mg or less of the API, for example 5 mg or less of the API.
  • Some solid phase dosage units, e.g. tablets contain 0.1 mg or more API (equivalent base weight), e.g. 0.2 mg or more of the API, for example 0.25 mg or more API.
  • There are therefore included in the invention dosage units e.g.
  • tablets which contain from 0.1 mg to 10 mg of the API (equivalent base weight), e.g. 0.2 mg to 7.5 mg of the API; particular dosage units, e.g. tablets, contain from 0.25 mg to 5 mg of the API (equivalent base weight), for example 2.5 mg to 5 mg of the API.
  • the dosage units e.g. tablets
  • the dosage units contain no more than 4 mg of the API (equivalent base weight), e.g. from 0.2 mg or 0.25 mg to 4 mg of the API.
  • Some dosage units contain from 2 mg or 2.5 mg to 4 mg of the API (equivalent base weight).
  • the dosage units contain 4 mg of the API.
  • the dosage units (e.g. tablets) mentioned in this paragraph comprise, or consist of, a solid phase mixture consisting of API and non-basic excipients which comprise a cellulosic excipient, e.g. selected from microcrystalline cellulose, hypromellose, ethylcellulose and combinations thereof.
  • the dosage units (e.g. tablets) mentioned in this paragraph comprise, or consist of, a solid phase mixture consisting of API and non-basic excipients which comprise a controlled release material, e.g. a non-basic hydrogel-former such as, for example, hypromellose.
  • the solid phase mixture may have at least one coating.
  • 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 all 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, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy, and in particular Y is phenyl substituted by a single said radical, e.g. by a single C 1-6 alkyl radical.
  • the designation “C 1-6 ” means “having 1, 2, 3, 4, 5 or 6 carbon atoms” and an exemplary C 1-6 alkyl radical is ethyl.
  • A-Z-C(R 4 )(R 3 )—Y— is
  • R 7 is H, halogen, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy, and in particular is C 1-6 alkyl e.g. ethyl.
  • W is C 1 , C 2 or C 3 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 C 1 , C 2 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 particular where A-Z-C(R 4 )(R 3 )—Y— may be
  • R 1 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, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or -C 1-6 alkoxy.
  • R 1 may therefore be phenyl substituted by C 3 -C 8 cycloalkyl, each optionally substituted as just mentioned; in one sub-embodiment, phenyl of R 1 is substituted by a single substituent, e.g. fluoro or in particular trifluoromethyl, and cycloalkyl of R 1 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 1 , C 2 or C 3 alkylene; Y is a phenyl group optionally substituted by 1, 2 or 3 radicals selected from halogen, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy; and R 1 is phenyl substituted by C 3 -C 8 cycloalkyl, wherein phenyl and cyclohexyl are each independently optionally substituted by 1 or 2 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or -C 1-6 alkoxy.
  • the invention in its various aspects 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 hemifumarate salt of 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 composition.
  • API active pharmaceutical ingredient
  • the composition is substantially dry, e.g. is made of substantially moisture-free constituents, 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.
  • embodiments of the invention lie in solid phase compositions, for examples 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; (2) 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 ⁇ m e.g. at least 10 ⁇ m; (3) the API is in the form of particles having an X90 diameter of at least 8 ⁇ m e.g. at least 10 ⁇ m and a crystallinity of 80% or more; (4) the API is not exposed to basic compounds, e.g.
  • the API is in the form of particles having an X90 diameter of at least 8 ⁇ m e.g. at least 10 ⁇ m 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; (6) any of (1), (2), (3), (4) and (5) in combination with provision of a moisture-protective layer or coating.
  • the above-mentioned APIs have poor stability in admixture with one or more of the following compounds; 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 gelatin.
  • the API is in a mixture of materials which is free of basic compounds.
  • the composition is free of basic compounds.
  • 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 and a second part does not incorporate a compound of formula A1 or A2 but does incorporate a basic compound.
  • 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 R 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 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 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 release 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 APIs in addition to one or more APIs of formula A1 or A2.
  • the composition 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 WO1996/001874, 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 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 excipients selected from lactose (e.g. as lactose monohydrate); microcrystalline cellulose; non-basic polymers e.g. homopolymers of cross-linked N-vinyl-2-pyrrolidone (crospovidone), hypromellose (hydroxypropylmethyl cellulose), and ethyl cellulose; waxes; colloidal silicon dioxide; stearic acid; hydrogenated vegetable oil; mineral oil; polyethylene glycol (e.g.
  • lactose 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, 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. Hydrogenated vegetable oils may act as controlled release agents.
  • the pharmaceutical composition comprises, or consists of, a solid phase mixture consisting of API and non-basic excipients which comprise a cellulosic excipient, e.g. selected from microcrystalline cellulose, hypromellose, ethylcellulose and combinations thereof.
  • the pharmaceutical composition comprises, or consists of, a solid phase mixture consisting of API and non-basic excipients which comprise a controlled release material, e.g. a non-basic hydrogel-former such as, for example, hypromellose.
  • the solid phase mixture may have at least one coating.
  • An embodiment of the invention therefore comprises 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 (e.g. as lactose monohydrate); microcrystalline cellulose; a polymer selected from homopolymers of cross-linked N-vinyl-2-pyrrolidone (crospovidone), hypromelloses, and ethyl cellulose; waxes, colloidal silicon dioxide; and a lubricant selected from stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol (e.g.
  • 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 admixture with: lactose (e.g. as lactose monohydrate); microcrystalline cellulose; a polymer selected from homopolymers of cross-linked N-vinyl-2-pyrrolidone (crospovidone) and hypromelloses; colloidal silicon dioxide; and a lubricant selected from hydrogenated vegetable oil, mineral oil, polyethylene glycol (e.g.
  • polyethylene glycol 4000-6000 polyethylene glycol 4000-6000
  • gyceryl palmitostearate and glyceryl behenate
  • combinations of the aforesaid lubricant compounds are present in the solid phase mixture, particularly glyceryl behenate.
  • an aspect 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 the hemifumarate salt of 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic 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 USP, EP and JP harmonised content uniformity requirement, e.g. as in force on 1 Jan. 2011.
  • the hemifumarate salt of 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 relating to particle size may therefore be beneficially applied to any such compound as an active pharmaceutical ingredient (API) of a composition.
  • the invention therefore provides a solid phase 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 8 ⁇ m and often of 10 ⁇ m or more, for example 20 ⁇ m or 25 ⁇ m or more, optionally of 100 ⁇ m or more and further optionally of 150 ⁇ m or more.
  • the particle size (X90 diameter) may be up to 300 ⁇ m, e.g. up to 250 ⁇ m, and optionally up to 200 ⁇ m (e.g. up to 195 ⁇ m).
  • the X90 diameter is of from 10 ⁇ m to 300 ⁇ m, e.g. 10 ⁇ m to 250 ⁇ m or 10 ⁇ m to 200 ⁇ m. Also included are embodiments in which the particle size (X90 diameter) is from 25 ⁇ m to 300 ⁇ m, e.g.
  • the X90 diameter is from 100 ⁇ m to 300 ⁇ m, e.g. 100 ⁇ m to 250 ⁇ m or 100 ⁇ m to 200 ⁇ m.
  • the X90 particle diameter is at least 10 ⁇ m and is less than 191 ⁇ m, e.g. less than 180 ⁇ m, less than 170 ⁇ m, less than 160 ⁇ m, less than 150 ⁇ m, less than 140 ⁇ m or less than 130 ⁇ m, e.g.
  • the X90 particle diameter is at least 25 ⁇ m and is less than 191 ⁇ m, e.g. less than 180 ⁇ m, less than 170 ⁇ m, less than 160 ⁇ m, less than 150 ⁇ m, less than 140 ⁇ m or less than 130 ⁇ m, e.g. no more than 125 ⁇ m, such as no more than 121 ⁇ m.
  • the X90 particle diameter is at least 10 ⁇ m or 25 ⁇ m but no more than 100 ⁇ m, e.g.
  • the X90 particle diameter is from 121 ⁇ m to 191 ⁇ m. In another embodiment, the X90 particle diameter is from 11 ⁇ m to 29 ⁇ m.
  • An aspect 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 8 ⁇ m 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 Jan. 2011.
  • the 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 ⁇ m complied with the harmonised content uniformity requirement whereas API particles having an X90 diameter of 191 ⁇ m failed to comply.
  • API particles having an X90 diameter of up to 191 ⁇ m 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 empirically.
  • 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.
  • Content uniformity testing is used to test the active content within individual units post-manufacturing (such as the content of active agents within individual tablets after compression).
  • 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.
  • a solid phase pharmaceutical composition in unit dosage form 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 Jan. 2011; 2) 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 6 mg API (equivalent base weight), the API being as particles have an X90 diameter of at least 100 ⁇ m but no more than 300 ⁇ m, e.g.
  • 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 0.2 mg to 1 mg API (equivalent base weight), the API being as particles have an X90 diameter of at least 10 ⁇ m but no more than 100 ⁇ m, e.g.
  • 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.
  • 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 the hemifumarate salt of 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.
  • the above salt of 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 composition.
  • the invention therefore provides a 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.
  • An 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 10 ⁇ m or more and particularly 11 ⁇ m or more, for example 20 ⁇ m or 25 ⁇ m or more, optionally of 100 ⁇ m or more and further optionally of 150 ⁇ m or more.
  • the X90 diameter may be as previously described herein under the heading “Particle Size”.
  • Crystallinity may be measured using any suitable means, for example 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 moisture barrier film, to the compressed tablet.
  • a film coating for example a moisture barrier film
  • API particles can be prepared by suitable milling techniques, e.g. those well known in the art such as, for example, wet-jet milling, pin-milling, and wet-ball milling
  • the coarse crystals may be obtained using any suitable methodolgy.
  • a solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“API”) which is a compound of formula A1 or A2 or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein the API is not exposed to a basic compound:
  • API active pharmaceutical ingredient
  • A is COOR 5 , OPO(OR 5 ) 2 , PO(OR 5 ) 2 , SO 2 OR 5 , POR 5 OR 5 or 1H-tetrazol-5-yl, R 5 being H or an ester-forming group;
  • W is a bond, C 1-3 alkylene or C 2-3 alkenylene;
  • Y is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy;
  • Z is chosen from:
  • R 6 is chosen from hydrogen and C 1-6 alkyl; and J 1 and J 2 are independently methylene or a heteroatom chosen from S, O and NR S ; wherein R 5 is chosen from hydrogen and C 1-6 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 ring; R 1 is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloooalkyl or C 3-8 heterocyclo
  • composition of numbered paragraph 1 or 2 wherein the compound is of formula A1.
  • a composition of numbered paragraph 1 wherein the API is 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid or a pharmaceutically acceptable salt.
  • a composition of numbered paragraph 1 wherein the API is 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid or a hemifumarate salt thereof.
  • composition of any preceding numbered paragraph which is a tablet.
  • composition of numbered paragraph 8 wherein the tablet is coated with a moisture barrier 8.
  • a composition of numbered paragraph 8 or 9 wherein the tablet comprises a solid phase mixture which consists of the API in admixture with: lactose; microcrystalline cellulose; a polymer selected from homopolymers of cross-linked N-vinyl-2-pyrrolidone (crospovidone) and hypromelloses; colloidal silicon dioxide; and a lubricant selected from hydrogenated vegetable oil, mineral oil, polyethylene glycol, gyceryl palmitostearate and glyceryl behenate.
  • crospovidone cross-linked N-vinyl-2-pyrrolidone
  • colloidal silicon dioxide colloidal silicon dioxide
  • a lubricant selected from hydrogenated vegetable oil, mineral oil, polyethylene glycol, gyceryl palmitostearate and glyceryl behenate.
  • a solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“API”) selected from the compounds as defined in any of numbered paragraphs 1 to 6, wherein the API is in the form of particles having an X90 diameter of at least 8 ⁇ m.
  • API active pharmaceutical ingredient
  • 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 Jan. 2011.
  • a composition of numbered paragraph 15 which is in the form of a tablet containing from 4 mg to 6 mg API (equivalent base weight) and particles have an X90 diameter of at least 100 ⁇ m but no more than 200 ⁇ m.
  • 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 least 10 ⁇ m but no more than 50 ⁇ m.
  • 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.
  • a solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“API”) selected from the compounds as defined in any of numbered paragraphs 1 to 6, wherein the API has a crystallinity of 80% or more.
  • API active pharmaceutical ingredient
  • composition of numbered paragraph 19 or 20 which is a tablet is a composition of numbered paragraph 19 or 20 which is a tablet.
  • composition of any of numbered paragraphs 18 to 21 which further includes the features of any one of, or any combination permitted by dependency of, of numbered paragraphs 1 to 10 and 11 to 17.
  • 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 a pharmaceutically acceptable salt thereof and one or more non-basic excipients, 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 diameter of from 10 ⁇ m to 200 ⁇ m.
  • Example 1 illustrates the stability of the hemifumarate salt of 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid in the presence of various compounds.
  • Mixtures of this API 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 API degradation and sum of degradation products were assayed. The results are displayed 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-acetonitrile containing 0.2% (v/v) formic acid and 10% (v/v) Triethylamine.
  • NVS-A The hemifumarate salt of 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid is described as “NVS-A” in Table 1.
  • a film coated tablet containing NVS-A was developed 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 as shown in Table 2 below.
  • 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).
  • ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • 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.
  • the finer API material (X 90 ⁇ 10 ⁇ m (4 and 7 ⁇ m) 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 11, 29 ⁇ m and 121 ⁇ m was obtained by milling in this case with a pin mill with the relative tin speed being adjusted from 115, to 75 to 40 m/sec respectively.
  • the coarser material with X 90 ⁇ m of 191 um was obtained by sieving on a 457 um sieve. The results are presented in FIG. 1 .
  • the drug substance particle sizes considered showed reduced impact on the mean content uniformity value and its variability for the 5 mg tablet:
  • the following example compares the sum of degradation products of four different compositions, each comprising 0.25 mg (equivalent free base weight) of the hemifumarate salt of 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid (NVS-A) mixed with a lubricant.
  • API drug particles were obtained and measured as in Example 3.
  • 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
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US10786500B2 (en) 2015-07-03 2020-09-29 Astellas Pharma Inc. Stable pharmaceutical composition for oral administration
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EP3318259B1 (de) 2015-07-03 2023-01-11 Astellas Pharma Inc. Stabile pharmazeutische zusammensetzung zur oralen verabreichung
EP4230208A1 (de) * 2015-07-03 2023-08-23 Astellas Pharma Inc. Stabile pharmazeutische zusammensetzung zur oralen verabreichung
US11938131B2 (en) 2015-07-03 2024-03-26 Astellas Pharma Inc. Stable pharmaceutical composition for oral administration
US11938132B2 (en) 2015-07-03 2024-03-26 Astellas Pharma Inc. Stable pharmaceutical composition for oral administration
US11938133B2 (en) 2015-07-03 2024-03-26 Astellas Pharma Inc. Stable pharmaceutical composition for oral administration
US11938130B2 (en) 2015-07-03 2024-03-26 Astellas Pharma Inc. Stable pharmaceutical composition for oral administration
US11944620B2 (en) 2015-07-03 2024-04-02 Astellas Pharma Inc. Stable pharmaceutical composition for oral administration
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