AU2011100879B4 - Oral formulations - Google Patents

Abstract

A solid pharmaceutical composition suitable for oral administration, comprising: 5 (a) a SiP receptor agonist, (b) a sugar alcohol; and (c) a pigment.

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION INNOVATION PATENT Name of Applicant: Novartis AG, of Lichtstrasse 35, Basel CH-4056, Switzerland Actual Inventors: Ann COMFORT; and Irene HUNT Address for Service: DAVIES COLLISON CAVE, Patent Attorneys, of 1 Nicholson Street, Melbourne, Victoria 3000, Australia Invention Title: "Oral formulations" The following statement is a full description of this invention, including the best method of performing it known to us: CNEponbjhCC\DA\ S255_.DOC .. 14/7/11 - 1 Oral formulations The present invention relates to pharmaceutical compositions comprising 2-amino-2-[2-(4 octylphenyl)ethyl]propane-1,3-diol (FTY720, INN fingolimod) which are suitable for oral 5 administration. FTY720 (fingolimod) became the first oral drug approved to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis (MS), under the tradename Gilenya m . The recommended dose of GilenyaTM is 0.5mg once daily. Before 10 FTY720, the MS drugs on the markets are all delivered by frequent injections, either intravenously or intra-muscularly, varying from once-per-day to once-per-week depending on the drug. Multiple sclerosis is an immune-mediated disease of the central nervous system white 15 matter with chronic inflammatory demyelination leading to progressive decline of motor and sensory functions and permanent disability. Manifestations of clinical disease usually begin in early adulthood, with women outnumbering men 2:1. The therapy of multiple sclerosis is only partially effective, and in most cases only offers a delay in disease progression despite anti-inflammatory and immunosuppressive treatment. Clinicians 20 usually categorize patients into four types of disease patterns: - Relapsing-remitting (RR-MS): Discrete motor, sensory, cerebellar or visual attacks that occur over 1-2 weeks and often resolve over 1-2 months, with or without treatment. Some patients accrue disability with each episode, yet remain clinically stable between relapses. About 85% of patients initially experience the RR form of MS, but within 10 25 years about half will develop the secondary progressive form. * Secondary-progressive (SP-MS): Initially RR followed by gradually increasing disability, with or without relapses. Major irreversible disabilities appear most often during SP. * Primary-progressive (PP-MS): Progression disease course from onset without any 30 relapses or remissions, affecting about 15% of MS patients. . Progressive-relapsing (PR-MS): Progressive disease from onset with clear acute -2 relapses; periods between relapses characterized by continuing progression. Oral solid medications, such as capsules or tablets, are viewed by customers as the most efficient method for taking medicine. As a consequence, many drugs but also OTC 5 products, including many analgesics, are in the form of capsules or tablets. Thus it becomes common for patients to have to take several medications which are all in the same format. This may become problematic for MS patients since it is the first time that a MS drug is oral, and thus could be mixed up with another oral medication, for example with an analgesic. Furthermore, patient-related reasons, such as visual impairment, cognitive 10 dysfunction, clumsiness, and tremor, may predispose to medication errors. Therefore there is a need for the patient to distinguish oral medications which are fingolimod-containing compositions, in particular in case of solid formulations, such as capsules or tablets, in order to minimize the potential for medication errors. 15 Furthermore because initiation of fingolimod treatment may result in a decrease in heart rate of the patient, specific precautions have to be taken for the first administration of fingolimod : the patients may have to be observed for several hours for signs an symptoms of bradycardia. If fingolimod treatment is discontinued for a while, e.g. for more than 2 20 weeks, the effects on heart rate may occur on reintroduction of fingolimod treatment and the same precautions as for initial dosing may apply. Therefore there is a strong need to increase fingolimod treatment compliance and adherence, and prevent patients who are under fingolimod treatment to stop taking their medication. 25 The present invention provides a solid pharmaceutical composition suitable for oral administration, comprising FTY720, a sugar alcohol comprising mannitol, and a pigment comprising titanium dioxide. The present invention father provides a kit comprising a pack and a plastic packaging, wherein each plastic packaging comprises such solid pharmaceutical compositions, for example capsules. 30 It has been found that kits of the invention, and solid fingolimod-containing compositions -3 are particularly well suited to the oral administration of FTY720, have good physicochemical and storage properties and can be easily distinguished from other concomitant drugs. Such compositions can be designed and colored in such a way that the patient can instantly recognize fingolimod from other concomitant drugs. The present 5 invention also permits to clearly mark the strength of the drug on each composition. Furthermore the present invention has the advantage of providing attractive solid compositions and packages, such as colored capsules and adequate packs, facilitating patient compliance and treatment adherence. 10 The solid compositions of the present invention have good physicochemical and storage properties. In particular, the compositions of the present invention may show a high level of uniformity in the distribution of FTY720 throughout the composition, as well as high stability. The compositions of the invention may be manufactured on high speed automated equipment, and thus do not require hand encapsulation. 15 Furthermore, the compositions of the invention may be packaged into packaging which provide barrier protection for shelf life requirements, and a degree of tamper resistance, such as blister. 20 FTY720, i.e. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form, e.g. the hydrochloride, as shown: HO- OH In another embodiment of the invention, FTY720 is in the form of the phosphate derivative 25 thereof, i.e. FTY720-phosphate 0--- -- OH OH M N S H:\rbr\Intenvoven\NRPortbl\DCC\RBR\5825843 _.DOC-18/1l/2013 -4 The composition of the invention may contain 0.01 to 20% by weight of fingolimod (FTY720), a salt, a phosphate derivative thereof, for example 0.1 to 10%, e.g. 0.5 to 5% by weight, based on the total weight of the composition. 5 In one aspect, the present invention provides a method for preventing or treating multiple sclerosis in a population of subjects in need thereof, comprising administering to said population a solid pharmaceutical composition suitable for oral administration, comprising: (a) 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form, in a 10 pharmaceutically acceptable salt form or a phosphate derivative thereof, (b) mannitol, (c) pigment comprising titanium dioxide and at least another pigment selected from yellow iron oxide, black iron oxide and a mixture thereof, and 15 (d) a lubricant, wherein said pharmaceutical composition is in the form of a bicolor capsule and said pigment is present in an amount of 0.02 to 5.5% by weight. In one embodiment of the invention, the pharmaceutical composition, e.g. each unit dosage 20 form, comprises 0.5 to 10 mg of fingolimod (FTY720), e.g. about 0.5mg of fingolimod (FTY720), e.g. about 0.56 mg of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride. Examples of pharmaceutically acceptable salts of the compounds of FTY720 include salts 25 with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals, such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. The compounds and salts of the present invention encompass 30 hydrate and solvate forms.

H.\br\lntenvoven\NRPorlbl\DCC\RBR\5825843_I.DOC-18/ 1/2013 - 4a The sugar alcohol, e,g. mannitol, e.g. D-mannitol, may act as a diluent, carrier, filler or bulking agent. Mannitol, can be used as a single sugar alcohol, or can be mixed with another sugar alcohol, e.g. with xylitol, e.g. in a ratio of 1:1 to 4:1. Other sugar alcohols may be maltitol, inositol, xylitol or lactitol, for example substantially non-hygroscopic 5 sugar alcohols. In one particular embodiment of the invention, the sugar alcohol is mannitol, e.g. D-mannitol. In a particularly preferred embodiment, mannitol is prepared from a spray-dried composition, having a high specific surface area. The use of this type of mannitol 10 composition may assist in promoting uniform distribution of FTY720 throughout the mannitol in the composition. A higher surface area may be achieved by providing a mannitol, preparation consisting of particles having a smaller mean size and/or a rougher surface on each particle. The use of a spray-dried mannitol, e.g. with a mean particle size of 300 pm or less, has also been found to improve compressibility and hardness of tablets -5 formed from the composition. In a specific embodiment of the invention, the single point surface area of the mannitol preparation is 1 to 7 m2/g, e.g. 2 to 6 m 2 /g or 3 to 5 m 2 /g. The mannitol preparation may 5 suitably have a mean particle size of 100 to 300 gm, e.g. 150 to 250 pm and a bulk density of 0.4 to 0.6 g/mL, e.g. 0.45 to 0.55 g/mL A suitable high surface area mannitol is Parteck M200, available commercially from E. Merck. In one embodiment of the invention, the composition contains 75 to 99.99% by weight of 10 the mannitol, for example 85 to 99.9%, e.g. 90 to 99.5% by weight, based on the total weight of the composition. The composition of the invention may contain 0.02 to 5.5% by weight of dyes, e.g. pigment, for example e.g. 0.05 to 5.0% by weight, 0.10 to 4.5% by weight, e.g. 0.15 to 15 4.0% by weight, e.g. 0.20 to 3.5% by weight, e.g. 0.50 to 3.0% by weight e.g. I to 2.5% by weight based on the total weight of the composition. The pigment may be selected from titanium dioxide, yellow iron oxide, black iron oxide and a mixture thereof. Preferably, the pigment is a combination comprising a) titanium 20 oxide with b) at least another pigment selected from yellow iron oxide, black iron oxide and a mixture thereof In a specific embodiment of the invention, the pigment is a mixture of titanium oxide, yellow iron oxide and black iron oxide. In another embodiment of the invention, the pigment is a mixture of titanium oxide and yellow iron oxide. 25 In one embodiment of the invention, the ratio titanium dioxide:yellow iron oxide may be from 10:1 weight by weight to 1:1, from 9:1 weight by weight to 2:1, e.g. 8:1 weight by weight to 6:1, e.g. about 7:1 weight by weight, e.g. about 6:1 weight by weight, e.g. about 5:1 weight by weight. 30 In one embodiment of the invention, the composition may further comprise ink, e.g. printing ink, e.g. black ink, yellow ink or mixture thereof.

-6 The composition may comprise one or more imprints. Such imprint may be e-g. radial imprint, radial bands, e.g. I to 4 bands, e.g. two radial bands, or mixture of radial imprint and radial band(s). The imprints made of different colored ink, for example the imprint, 5 e.g. radial imprint, may be made with black ink, the radial bands, e.g. two radial bands may be made with yellow ink. In addition or instead, the imprint may contain any letters or figures, e.g. any one of "F", "T', "Y", 47", "2", "0", e.g. "FTY720" or "FTY". The composition may also contain the marking of the strength, e.g. "0.5mg", imprinted on the body of the composition. For example, the composition contains the imprint "FTY 0.5mg" 10 or "FTY720 0.5mg". The imprint "FTY 0.5mg" or "FTY720 0.5mg may e.g. be in black or in yellow. For example, the capsules of the invention are marked using a code. 15 The composition may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g. Cutina@ or Lubriwax@ 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium 20 benzoate, talc, poloxamer, or a mixture of any of the above. For example the lubricant comprises magnesium stearate, hydrogenated castor oil or mineral oil. Colloidal silicon dioxide and polyethylene glycol are less preferred as the lubricant. The composition may contain 0.01 to 5% by weight of the lubricant, for example 1 to 3% 25 by weight, e-g. about 2% by weight, based on the total weight of the composition. The composition may comprise one or more further excipients such as carriers, binders or diluents. In particular, the composition may comprise microcrystalline cellulose (e-g. Avicel®), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch 30 (e.g. corn starch) or dicalcium phosphate, for example in an amount of from 0.1 to 90 % by weight, e.g. I to 30% by weight, based on the total weight of the composition. Where a -7 binder, e.g. microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose is used, it is for example included in an amount of 1 to 8 %, e.g. 3 to 6% by weight, based on the total weight of the composition. The use of a binder increases the granule strength of the formulation, which is particularly important for 5 fine granulations. Microcrystalline cellulose and methylcellulose are particularly preferred where a high tablet hardness and/or longer disintegration time is required. Hydroxypropyl cellulose is preferred where faster distintegration is required. Where appropriate, xylitol may also be added as an additional binder, for example in addition to microcrystalline cellulose, e.g. in an amount up to 20% by weight of the sugar alcohol, e.g. xylitol. 10 In one embodiment, the composition further comprises a stabiliser, for example glycine HCl or sodium bicarbonate. The stabiliser may be present in an amount of e.g. 0.1 to 30%, for example I to 20% by weight. 15 The composition may be in the form of a powder, granule or pellets or a unit dosage form, for example as a tablet or capsule. In a specific embodiment, the compositions of the present invention are encapsulated into an orally administrable capsule shell, e.g. a hard gelatin shell. 20 In one embodiment of the invention, the composition is in the form of a bicolor capsule, e.g. a bicolor gelatin capsule. The cap and the body of the capsule may have a different color, e.g. may contain different dyes or pigments or different ratios thereof. For example, one part of the capsule, e.g. the body, contains essentially titanium dioxide as pigment, and the other part of the capsule, e.g. the cap, contains a mixture of titanium dioxide and 25 yellow iron oxide, and optionally black iron oxide. In one example, the capsule comprises a white body and a yellow or orange cap, e.g. a white opaque body and a yellow opaque or orange opaque cap. The imprinting may also be different on the two parts of the capsule or can be present only 30 in one part of the capsule. One part of the capsule, e.g. the cap, may comprise a radial imprint with letters as defined above, e.g. "FTY 0.5mg". The capsule may contain one or more radial bands imprinted on the body. In a specific embodiment, the color of the imprint is different on the cap and the body. For example, the imprint on one part of the capsule is black on the imprint on the second part is 5 yellow or orange. In one example, the imprint on the cap is black, and the imprint on the body is yellow or orange, e.g. the cap comprises the imprint "FTY 0.5mg" in black, and the body comprises one or more radial bands in yellow or orange, eg, I to 4 bands, e.g. 2 bands. 10 In one embodiment of the invention, the composition may further comprise ink, e.g. printing ink, e.g. black ink, yellow ink or mixture thereof. In another embodiment, the capsule comprises one imprint on the cap and one on the body, both imprints being black, yellow or orange. For example the capsule comprises the 15 imprint "FTY 0.5mg" in one part, e.g. the cap, and one or more radial bands, e.g. 1 to 4 bands, e.g. 2 bands, on the body, both the imprint "FTY 0.5mg" and the bands being black or yellow Alternatively the compositions may be compacted into tablets. The tablets may optionally 20 be coated, for instance with tale or a polysaccharide (e.g. cellulose) or hydroxypropylmethylcellulose coating. Where the pharmaceutical composition is in unit dosage form, e.g. a capsule or a tablet, e.g. a gelatin capsule, each unit dosage may suitably contain 0.5 to 10 mg of FTY720, e.g. 25 about 0.5 mg of FTY720. Each unit dosage form, e.g. each capsule or a tablet, e.g. each gelatin capsule may comprise about 0.56 mg of 2-amino-2-[2-(4 octylphenyl)ethyl]propane-1,3-diol hydrochloride. The compositions of the invention may show good stability characteristics as indicated by 30 standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics may be determined, e.g. by measuring -9 decomposition products by HPLC analysis after storage for particular times, at particular temperatures, e.g. 20*, 400 or 60 0 C. The pharmaceutical compositions of the present invention may be produced by standard 5 processes, for instance by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Procedures which may be used are known in the art, e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharruazeutische Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's 10 Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions. In one aspect, the present invention relates to a process for producing a pharmaceutical composition, comprising: (a) mixing an Si P receptor agonist with mannitol; 15 (b) milling and/or granulating the mixture obtained in (a); (c) adding a pigment optionally comprising titanium dioxide, and optionally (d) imprinting the composition. The process may comprise a further step, step (b') between steps (b) and (c), consisting of 20 mixing the milled and/or granulated mixture obtained in (b) with a lubricant. By using this process, a preparation having a good level of content and blend uniformity (i.e. a substantially uniform distribution of the SIP receptor agonist throughout the composition), dissolution time and stability is obtained, as well as a preparation which can 25 easily be distinguished from the other oral compositions. FTY720, e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride, may optionally be micronized, and/or pre-screened, e.g. with a 400 to 500 pm mesh screen, before step (a) in order to remove lumps. The mixing step (a) may suitably comprise 30 blending FTY720 and the sugar alcohol, e.g. mannitol in any suitable blender or mixer for e.g. 100 to 400 revolutions.

-10 The process may be carried out by dry mixing the components. In this embodiment the milling step (b) may suitably comprise passing the mixture obtained in (a) through a screen, which for example has a mesh size of 400 to 500 pm, Process step (a) may 5 comprise the step of mixing the total amount of FTY720 at first with a low amount of the sugar alcohol, e.g. from 5 to 25% by weight of the total weight of sugar alcohol, in order to form a pre-mix. Subsequently the remaining amount of sugar alcohol is added to the pre mix. Step (a) may also comprise the step of adding a binder solution, e.g. methylcellulose and/or xylitol, e.g. an aqueous solution, to the mixture. Alternatively the binder is added to 10 the mix dry and water is added in the granulation step. The milled mixture obtained in (b) may optionally be blended once more before mixing with the lubricant. The lubricant, e.g. magnesium stearate, may be pre-screened, e.g. with a 800 to 900 gm screen, before mixing. 15 Alternatively, a wet granulation process is employed. In this embodiment, FTY720 is for example first dry-mixed with the desired sugar alcohol, e.g. mannitol, and the obtained sugar alcohol/S1P receptor agonist mixture is then dry-mixed with a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose. Water is then added and the 20 mixture granulated, e.g. using an automated granulator. The granulation is then dried and milled. If desirable, an additional amount of binder may be added in step (b') to the mixture obtained in (b). 25 The process may comprise a further step of tabletting or encapsulating the mixture obtained in (b) or (b'), e.g. into a hard gelatin capsule using an automated encapsulation device. 30 Step (c) may comprise or consist of coloring the composition, e.g. the tablet or capsule, by adding pigments. Such pigment may comprise titanium dioxide, yellow iron oxide, black - 11 iron oxide or mixture thereof, e.g. titanium dioxide. When the composition is in form of a capsule, e.g. a hard gelatin capsule, step (c) may consist of adding the pigment to the capsule shell. Step (c) may also consist of 5 encapsulating the mixture obtained in step (b) or in step (b'), preferably in step (b'), into an empty capsule shell comprising a pigment, e.g. titanium dioxide, and then closing the capsule with a capsule cap. The capsule cap may be pre colored with a pigment, e.g. titanium dioxide, yellow iron oxide, black iron oxide or mixture thereof In a specific embodiment of the invention, the capsule cap comprises a pigment or a pigment mixture 10 which is different to the pigment, or pigment mixture, comprised in the capsule shell. Step (d) may consist of printing the capsule after it has been filled in with the mixture obtained in step (b) or in step (b'), preferably in step (b'), using an automated printing device. Step (d) may also consist of using a pre-print capsule, e.g. a pre-print capsule shell 15 and/or a pre-print capsule cap, for the encapsulation. The empty capsule shell and the empty capsule cap may be printed or pre-printed with a printing ink, e.g. yellow printing ink, black printing ink or mixture thereof. 20 In a specific embodiment, the compositions of the invention are packaged into plastic packaging, such as blister pack. The blister may comprise 7, 28 or 84 compositions of the present invention in the form of unit dosage, e.g. capsules, e.g. gelatin capsules. The blister packs may be created through a form-fill-seal process, i.e. the blister pack may 25 be created from rolls of flat sheet or film, filled with the compositions of the invention and closed, e.g. sealed, on the same equipment. The pharmaceutical compositions of the present invention are useful, either alone or in combination with other active agents, for 30 a) treating or preventing multiple sclerosis, e.g. Relapsing Remitting multiple sclerosis or Secondary Progressive multiple sclerosis, in particular in patients under - 12 fingolimod treatment; b) reducing, preventing or alleviating relapses of multiple sclerosis, e.g. Relapsing Remitting multiple sclerosis or Secondary Progressive multiple sclerosis, in particular in patients under fingolimod treatment; 5 c) increasing, improving or maintaining multiple sclerosis treatment compliance in patients affected by multiple sclerosis, e.g. Relapsing Remitting multiple sclerosis or Secondary Progressive multiple sclerosis, in particular in patients under fingolimod treatment; d) increasing, improving or maintaining multiple sclerosis treatment adherence in 10 patients affected by multiple sclerosis, e.g. Relapsing Remitting multiple sclerosis or Secondary Progressive multiple sclerosis, in particular in patients under fingolimod treatment; e) preventing patients affected by multiple sclerosis, e.g. Relapsing Remitting multiple sclerosis or Secondary Progressive multiple sclerosis, from quitting or 15 stopping multiple sclerosis treatment, in particular patients under fingolimod treatment. Accordingly, in further aspects the present invention provides: 20 1. A plastic packaging, e.g. a blister, comprising a pharmaceutical composition as defined above. 2. A kit comprising a pack and a plastic packaging, e.g. a blister, wherein said blister comprises comprising a pharmaceutical composition as defined above. 25 3. A composition as defined above, a plastic packaging as defined under point I above or a kit as defined under point 2 above, for use in treating or preventing a disease or condition as defined above. 30 4. A method of treating a subject affected by multiple sclerosis, e.g. Relapsing Remitting multiple sclerosis or Secondary Progressive multiple sclerosis, comprising - 13 administering to the subject an effective amount of a composition as defined above. 5. A method of increasing, improving or maintaining multiple sclerosis treatment compliance in a population of patients affected by multiple sclerosis, in particular patients 5 under fingolimod treatment, said method comprising prescribing to the population composition as defined above, a plastic packaging as defined under point 1 above or a kit as defined under point 2 above. 6. A method for increasing, improving or maintaining multiple sclerosis treatment 10 adherence in a population of multiple sclerosis patients, in particular patients under fingolimod treatment, said method comprising prescribing to the population a composition as defined above, a plastic packaging as defined under point I above or a kit as defined under point 2 above. 15 7. A method for preventing patients affected by multiple sclerosis, in particular patients under fingolimod treatment, to quit or stop to take their multiple sclerosis treatment, said method comprising prescribing to the population a composition as defined above, a plastic packaging as defined under point I above or a kit as defined under point 2 above. 20 8- A method of treating or preventing a disease or condition as defined above, comprising administering to the subject a composition as defined above. 9. Use of a pharmaceutical composition as defined above for the preparation of a 25 medicament for the prevention or treatment of a disease or condition as defined above. The invention will now be described with reference to the following specific embodiments. Example 1 30 116.7 g of FTY720 and 9683.3 g of mannitol (Parteck M200 from E. Merck) are each screened separately using an 18 mesh screen before being mixed. The FTY720/mannitol - 14 mixture is then screened through a 35 mesh screen. Magnesium stearate is screened using a 20 mesh screen and 200 g of the screened compound blended with the FTY720/mannitol mixture to produce a product composition. 5 The product composition is then filled-in in empty capsule shell, each containing: FTY720* 0.56 mg Mannitol M200 46.48 mg Magnesium stearate 0.96 mg Total Capsule fill weight 48 mg 10 *1 mg of FTY720 in free form is equivalent to 1.12 mg of FTY720 hydrochloride. The empty capsule shell is pre-printed and comprises: Yellow iron oxide (E172) 0.164mg Titanium dioxide (E171) 1.022mg 15 Gelatin 46.810mg Printing ink, black q.s Printing ink, yellow q.s Capsule shell (total) 48.00mg Total Capsule weight 96.00mg 20 Example 2 FTY720, is screened using a 400 ptm (40 mesh) screen. 58.35 g of the screened compound is mixed with 4841.65 g mannitol (Parteck M200 from E. Merck) in a 25L Bohle bin blender for 240 blending revolutions. The mixture is then milled in a Frewitt MGI device 25 using a 400 pm mesh screen, and the milled mixture is blended once more. Magnesium stearate is screened and 100 g of the screened compound is blended with the FTY720/manitol mixture to produce a product composition showing a substantially uniform distribution of the SIP receptor agonist throughout the mannitol in the blend. 30 The product composition is then filled into size 3 hard gelatin shells, as defined in example 1, on an Hoflinger & Karg 400 encapsulation device 48 mg of the product composition is - 15 added to each capsule. Therefore each capsule contains: FTY720* 0.56 mg Mannitol M200 46.48 mg Magnesium stearate 0.96 mg 5 Total 48 mg Example 3 In an alternative embodiment, capsules are manufactured using the components and in the amounts as described in Example 2, but the FTY720 is first mixed with 14 mg mannitol 10 (before screening). This mixture is then screened as described above. The screened mixture is then blended with the remaining mannitol and the magnesium stearate is added, followed by additional blending and filling into colored and pre printed capsules, as in example 2. 15 Example 4 In further examples, capsules are prepared as described in example 2 or 3. The used capsules have a white opaque body and a bright yellow opaque cap. The cap contains a radial imprint with black ink "FTY 0.5 mg"; and the body contains two radial bands imprinted with yellow ink. 20 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 25 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of 30 endeavour to which this specification relates.

Claims (5)

1. A method for preventing or treating multiple sclerosis in a population of subjects in need thereof, comprising administering to said population a solid pharmaceutical 5 composition suitable for oral administration, comprising: (a) 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form, in a pharmaceutically acceptable salt form or a phosphate derivative thereof, (b) mannitol, (c) pigment comprising titanium dioxide and at least another pigment selected 10 from yellow iron oxide, black iron oxide and a mixture thereof, and (d) a lubricant, wherein said pharmaceutical composition is in the form of a bicolor capsule and said pigment is present in an amount of 0.02 to 5.5% by weight. 15

2. A method for reducing or preventing or alleviating relapses of multiple sclerosis, in a population of subjects in need thereof, comprising administering to said population a solid pharmaceutical composition suitable for oral administration as defined in claim 1. 20

3. A method of claim 1 or 2, wherein the pharmaceutical composition is in the form of a bicolor gelatin capsule, wherein the cap and the body of said capsule have a different color.

4. A method according to any one of the preceding claims, wherein the 25 pharmaceutical composition comprises 0.5 to 10 mg of 2-amino-2-[2-(4 octylphenyl)ethyl]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form.

5. A method according to any one of the preceding claims wherein the pharmaceutical 30 composition further comprises at least one of the features selected from a radial imprint "FTY 0.5mg" on the cap and one or more radial bands imprinted on the body.