CN117065037A

CN117065037A - Pharmaceutical compositions comprising S1P modulators

Info

Publication number: CN117065037A
Application number: CN202311044167.3A
Authority: CN
Inventors: M·安布尔; J·拜尔; B·卡雷尼奥-戈麦斯; C·吕埃格尔; S·瓦拉达
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-09-26
Filing date: 2007-09-25
Publication date: 2023-11-17

Abstract

The present application relates to pharmaceutical compositions comprising S1P modulators. The present application provides various pharmaceutical compositions comprising S1P receptor modulators, e.g., S1P agonists. In one aspect, the application provides a pharmaceutical composition having a coating. In other aspects, the application provides rapidly disintegrating compositions. In a further aspect, the application provides a pharmaceutical composition free of sugar alcohols. In another aspect, the application provides a pharmaceutical composition comprising a coating comprising an S1P receptor modulator.

Description

Pharmaceutical compositions comprising S1P modulators

The application is a divisional application of a Chinese patent application with the name of 'pharmaceutical composition containing S1P regulator' and application number 201510512294.0, which is filed on the 9 th month and 25 th 2007.

Technical Field

The present application relates to pharmaceutical compositions comprising sphingosine-1-phosphate receptor modulators, in particular sphingosine-1-phosphate receptor agonists.

Background

Sphingosine-1-phosphate (hereinafter referred to as "S1P") is a natural serum lipid. There are currently 8 known S1P receptors, S1P1 to S1P 8. S1P receptor agonists have the property of accelerating lymphocyte homing.

S1P receptor agonists are immunomodulatory compounds that elicit lymphopenia due to the redistribution (preferably reversible) of lymphocytes from the circulatory system to the second lymphoid tissue, thereby causing systemic immunosuppression. The naive cells are sequestered, and CD4 and CD 8T-cells and B-cells in the blood are stimulated to migrate into the Lymph Nodes (LN) and Peyer's Patch (PP), and thus inhibit infiltration of cells into the transplanted organ.

A variety of known S1P receptor modulators exhibit structural similarity, which causes related problems in providing suitable formulations. There is a need for formulations comprising S1P receptor modulators, which in solid form (e.g. tablets or capsules) are well suited for oral administration. In addition, the oral route is often the most convenient route in drug administration, but unfortunately many patients have difficulty swallowing due to, for example, unpleasant dosage form taste or the inability to obtain water upon administration. Thus, there remains a need for oral formulations comprising S1P receptor modulators that are easy to swallow, for example, by children or elderly patients. In addition, there is a need for a method of easily producing dosage forms of S1P receptor modulators with multiple dosage strengths.

Disclosure of Invention

The present invention provides a variety of pharmaceutical compositions comprising S1P receptor modulators that meet these needs. The compositions provide a convenient method of systemic administration of S1P receptor agonists and other modulators, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage characteristics. In particular, the compositions of the present invention may exhibit a high level of uniformity in the distribution of the S1P receptor modulator in the composition as well as high stability. The compositions of the present invention can be prepared on high-speed automated equipment and thus do not require manual encapsulation.

In certain aspects, the present invention provides fast-dispersing dosage forms that disintegrate rapidly in the mouth and do not rely on the use of sweeteners or flavoring agents to mask the taste, nor on the presence of liquids to flush the dosage form. These dosage forms are capable of disintegrating in the mouth, in particular in saliva. Preferably, the dosage form has a good mouthfeel and there is no premature release of the drug in the mouth. Rapid disintegration of the solid pharmaceutical composition may increase the solubility of the active ingredient. In particular in the case of saliva, it may lead to better solubility of the drug than in the small intestine.

The pharmaceutical compositions of the invention may be prepared by standard methods, for example by conventional mixing, granulating, dissolving, or lyophilizing processes. Methods that can be used are known in the art, for example, from L.Lachman et al, the Theory and Practice of Industrial Pharmacy (theory and practice of industrial pharmacy), 3 rd edition, 1986; sucker et al, pharmazeutische Technologie, thieme,1991; hagers Handbuch der pharmazeutischen Praxis, 4 th edition (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences (rest pharmaceutics), 13 th edition (Mack publication, co., 1970) or the latest versions.

The compositions of the invention exhibit good stability characteristics, for example having a shelf life stability of at most one, two or three years and even longer, as demonstrated by standard stability tests. Preferably, the composition is stable for at least six months at ambient temperature. Stability characteristics can be determined, for example, by measuring the decomposition products by HPLC analysis after storage at a particular temperature (e.g., 20 ℃, 40 ℃ or 60 ℃) for a particular time.

Composition comprising a coating

By applying a coating on a tablet or pellet core or capsule surface, the pharmaceutical composition can be made easier to swallow, thereby improving compliance by reducing or masking unpleasant taste.

In one aspect, the present invention provides an oral pharmaceutical composition comprising an S1P receptor modulator, e.g., an S1P receptor agonist, wherein the composition comprises a coating comprising:

(a) One or more polymer resins

(b) One or more metal oxides.

The solid composition may take the form of pellets of different sizes, wherein the coating is applied to individual pellets, which may be present in a plurality, for example in a capsule or sachet.

The solid composition may be formed from powder ingredients (which may be micronized) and may be compacted into compositions of varying hardness.

In one embodiment, the powder components of the compression composition are coated prior to compression.

In another embodiment, the compression composition is coated after compression.

In another embodiment, the coating is applied both before and after compression.

The liquid oral composition includes a capsule comprising the liquid composition, wherein the capsule comprises a coating.

In one embodiment, the coating is applied to the outer surface of the capsule.

In another embodiment, the coating is dispersed within the outer surface of the capsule.

However, capsules are not limited to liquid contents and may contain solid compositions in powder form, pellets or heterogeneous suspensions in addition to homogeneous liquids.

When the solid compositions are in the form of pellets or granules, they may be applied as such or filled into capsules, such as hard gelatin capsules, or other storage means, such as sachets, prior to application after application of the coatings described herein.

The diameter of the pellets and granules may be 2 to 0.3mm, for example the size of "standard pellets" is 1 to 0.6mm and the size of "beaded pellets" is 0.4 to 0.8mm.

The coating composition of the present invention is particularly suitable for use in tablet compositions, herein referred to and exemplified as core tablets.

In one embodiment, the coating composition is used to coat compressed tablet cores comprising an S1P modulator, e.g., an S1P agonist.

The tablet core may be any solid formulation for oral administration.

The term "tablet core" in a broad sense includes not only tablets, pellets or granules, but also capsules, for example soft or hard gelatin or starch capsules. Such tablet cores may be prepared in conventional manner.

When tablet cores are used, they preferably have a hardness of about 10 to 70N. The tablet core may have a tensile strength of less than 38N/cm ² For example as low as 22N/cm ² 。

The hardness of a core tablet comprising an S1P modulator, e.g. an S1P agonist, may be enhanced by applying a coating as described herein. Thus, the coating may be provided for use by having a coating with a thickness of less than 38N/cm ² A method of (2.5 kP) tensile strength tablet cores (i.e. otherwise the tablet cores are considered too soft in practical applications) to obtain tablets with good structural integrity. The tablet core may have a thickness of less than 30N/cm ² (2.0 kP), preferably less than 22N/cm ² (1.5 kP) tensile strength.

The tablet cores may be formed by light compaction and using the coating and friable components (e.g., capsules) in a compression blend (with little or no damage).

The core tablet may comprise an adjuvant and an S1P modulator, such as an S1P agonist.

The core tablet may contain conventional tabletting ingredients including diluents, disintegrants, lubricants, wetting agents, glidants, surfactants, release aids, colorants, effervescent agents, etc.

The chiplet may be formulated by any known formulation method known to the skilled artisan.

The core tablet may include, but is not limited to, fillers such as polyols, powdered mannitol, e.g., or other sugars or sugars, sugar alcohols, etc., such as lactose, sucrose, dextrose, mannitol, and starch.

The tablet core composition may also or alternatively comprise a binder such as PVP, for example cellulose, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, starch cement, acacia, alginic acid, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropyl methyl cellulose, magnesium aluminum silicate, kalto ctrin, methyl cellulose, polyethylene oxide, povidone, sodium alginate and hydrogenated vegetable oil.

The tablet core composition may also or alternatively comprise a disintegrant (with or without an effervescent agent), such as croscarmellose sodium (croscarmellose), crospovidone, or sodium starch glycolate.

The tablet core composition may also or alternatively comprise a lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal silicon dioxide or talc.

In one embodiment, the tableting agent comprises 1.5 to 2% lubricant, such as magnesium stearate or calcium stearate.

The chiplet composition may also or alternatively contain a glidant, such as silicon dioxide.

The tablet-core composition may also or alternatively comprise a surfactant, such as sodium lauryl sulfate or docusate sodium.

The tablet-core composition may also or alternatively comprise a flavoring agent.

The tablet core composition may also or alternatively comprise an effervescent agent, such as sodium bicarbonate or citric acid.

The tablet-chip composition may also or alternatively contain a sweetener.

The tablet core composition may also or alternatively comprise a pH adjuster, such as citric acid or fumaric acid.

The core tablet may contain release rate controlling additives. For example, the drug may be entrapped in a hydrophobic polymer matrix so as to be gradually released from the matrix upon contact with body fluids.

Alternatively, the drug may be entrapped in a hydrophilic matrix which dissolves gradually or rapidly in the presence of body fluids. Tablet cores may comprise two or more layers with different release characteristics. These layers may be hydrophilic layers, hydrophobic layers or a mixture of hydrophilic and hydrophobic layers. Adjacent layers in a multilayer tablet core may be separated by an insoluble barrier layer or a hydrophilic separator layer. The insoluble barrier layer may be formed from a substance used to form the insoluble shell. The hydrophilic release layer may be formed of a material that is more soluble than the other layers of the tablet core so that when the release layer dissolves, the release layer of the tablet core is exposed.

Suitable release rate controlling polymers include polymethacrylates, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, acrylic polymers, polyethylene glycol, polyethylene oxide, carrageenan, cellulose acetate, zein, and the like.

The chipper may also contain materials that swell upon contact with aqueous liquids and these materials may be included in the composition, including polymeric materials including croscarmellose sodium, croshydroxypropyl cellulose, high molecular weight hydroxypropyl cellulose, carboxymethyl amide, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone, and high molecular weight polyvinyl alcohol.

The chipsets may contain additional pharmaceutically active ingredients in addition to the S1P modulator, e.g., S1P agonist.

In one embodiment, when the tablet-and-chip composition is in unit dosage form, each unit dosage suitably comprises from 0.5 to 10mg of a S1P receptor modulator, e.g., S1P agonist.

Possible preparation of tablet cores involves mixing all ingredients and further compressing into tablets, and granulating and further compressing the granules into tablets.

In one embodiment, the present invention provides a tablet core composition comprising a sugar alcohol. Examples of tablet-and-chip formulations comprising S1P receptor modulators, e.g. S1P agonists, can be found in WO2004/089341, which describes formulations of S1P modulators with sugar alcohols.

The sugar alcohol may be used as a diluent, carrier, filler or bulking agent, and may suitably be mannitol, maltitol, inositol, xylitol or lactitol, preferably a sugar alcohol which is substantially non-hygroscopic, such as mannitol (D-mannitol). A single sugar alcohol, or a mixture of two or more sugar alcohols, for example a mixture of mannitol and xylitol, may be used, for example in a ratio of 1:1 to 4:1.

In another embodiment, the invention provides a tablet core composition comprising microcrystalline cellulose and an S1P receptor modulator, e.g., an S1P agonist, in the absence of a sugar alcohol.

Preferably, both the core tablet and the coating components are micronized.

In one embodiment, the solid formulation may be formulated to have a fast disintegration rate.

The preferred dosage range of the active ingredient is 0 to 1000mg.

The coating composition may be based on a powder or a liquid.

The coating composition may be of suitable electrical properties and be meltable at a temperature suitable for the coating substance used in the core coating of the pharmaceutical tablet.

Examples of polymer resins may include, but are not limited to, polymethacrylates such as ammonium methacrylate, cellulose and its derivatives, cellulose ethers and esters, and cellulose acetate phthalate.

Preferred polymer resins are non-conductive.

The coating composition may comprise polyethylene glycol or sugar alcohol, such as xylitol.

The coating composition may also or alternatively comprise other possible substances including waxes and oils or alcohols of waxes or oils, poloxamers, alkyl phthalates, such as diethyl phthalate, citric acid or esters.

The coating composition may also or alternatively comprise one or more polymers and copolymers of acrylic acid, acrylic acid and their derivatives, such as polymethyl acrylate, polyalkenes and their derivatives, including esters and aryl-esters and their derivatives, polyvinyl alcohol and esters, cellulose and its derivatives, such as cellulose ethers and cellulose esters (crosslinked or uncrosslinked), such as ethylcellulose, and one or more enteric polymers, such as cellulose acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, one or more biodegradable polymers, such as one or more polylactides, polyglycolides, polyhydroxybutyrate, polyhydroxyvalates, ethylene vinyl acetate copolymers and polyanhydrides (homo-or heteropolymers) or polyethylene oxides.

The coating composition may also or alternatively comprise a dispersing agent, such as sodium lauryl sulfate, sodium docusate, tween (sorbitan fatty acid ester), poloxamer and cetostearyl alcohol.

The coating composition may also or alternatively contain an anti-friction component to reduce friction and/or other forces between the powder coating material particles, thereby improving the flowability of the powder, such as titanium dioxide, colloidal silica, talc or starch or combinations thereof.

The coating composition may also or alternatively comprise a disintegrant, such as sodium starch glycolate (crosslinked), sodium carboxymethyl cellulose (crosslinked), natural starch, crosslinked polyvinylpyrrolidone (crosslinked povidone), sodium carbonate, sodium bicarbonate, or sodium glycinate.

The coating composition may also or alternatively comprise a colorant, such as a metal oxide or lake (e.g., an aluminum lake), iron oxide, or dye.

The coating composition may also or alternatively comprise taste modifiers such as aspartame, acesulfame potassium, cyclamate, saccharin, sugar or sugar alcohols.

The coating composition may also or alternatively comprise a flavouring agent.

In one embodiment, the coating comprises:

(a) Methacrylic acid copolymer

(b) Cellulose

(c) One or more metal oxides

The present invention also provides a method of preparing a coated pharmaceutical composition for oral administration, the method comprising:

(a) Preparing a core tablet comprising an S1P receptor modulator; and

(b) A coating as defined above is applied.

In one embodiment, the method comprises:

(a) Mixing an S1P receptor agonist or other modulator with a sugar alcohol;

(b) Grinding and/or granulating the mixture obtained in (a); and

(c) Mixing the milled mixture obtained in (b) with a lubricant;

(d) Optionally, additional solvents, flavors or preservatives in propylene glycol and added glycerin; and

(e) The coating composition of the present invention is applied.

By applying this method, a formulation is obtained that has a good level of content and mixing uniformity (e.g. S1P receptor modulator is substantially uniformly distributed in the composition), dissolution time and stability.

In the case of tablet core compositions comprising S1P receptor agonist (e.g. 2-amino-2- [2- (4-octylphenyl) ethyl ] propane-1, 3-diol, hydrochloride salt), the composition is optionally micronised prior to step (a) and/or pre-screened, e.g. with a 400 to 500 μm screen, to remove lumps. The mixing step (a) may suitably comprise mixing the S1P receptor agonist and the sugar alcohol (e.g. mannitol) in any suitable mixer or mixer, for example 100 to 400 revolutions.

The method may be carried out by dry mixing the components. In this embodiment, the milling step (b) may suitably comprise sieving the mixture obtained in (a), preferably in the size range 400 to 500 μm. Method step (a) may include a mixing step of first mixing the total amount of S1P receptor agonist or other modulator with a small amount of sugar alcohol, e.g., 5 to 25% by weight of the total weight of sugar alcohol, to form a premix. Subsequently, the remaining amount of sugar alcohol is added to the premix. Step (a) may further comprise the step of adding a binder solution, such as methylcellulose and/or xylitol, such as an aqueous solution, to the mixture.

The milled mixture obtained in (b) may optionally be mixed once more before mixing with the lubricant. The lubricant (e.g. magnesium stearate) is preferably pre-sieved, e.g. with a 800 to 900 μm sieve, before mixing.

Alternatively, a wet granulation process is applied. In this embodiment, the S1P receptor modulator is preferably dry mixed with the desired sugar alcohol, e.g., mannitol, and then the resulting sugar alcohol/S1P receptor modulator mixture is dry mixed with a binder, e.g., hydroxypropyl cellulose or hydroxypropyl methylcellulose. Water is then added and the mixture is granulated, for example using an automatic granulator. The particles are then dried and ground.

If desired, an additional amount of binder may be added to the mixture obtained in step (c).

The process may comprise further tabletting the mixture obtained in (c) or encapsulating in hard gelatine capsules, for example using an automatic encapsulating device. The capsules may be colored or marked so as to give the respective appearance and to make them immediately identifiable. The use of dyes can be used to enhance appearance and identify capsules. Pharmaceutically suitable dyes typically include carotenoids, iron oxides and chlorophyll. Preferably, the coding is applied to mark the capsules.

In particular, in the case of coated tablet cores, the coating mixture may be prepared by melt-extruding a mixture of polymer, coloring agent and other additives, and then further micronizing the resulting melt-extrudate is necessary (7 to 10 microns). The coating powder is stable in a suitable package and can be used to coat the product at least one year after production.

The coating extends over the tablet core due to electrostatic deposition of the powder comprising the fusible particles.

This technique results in a thin, continuous film on the surface of the tablet core. Typically, the film will cover 25 to 100%, preferably 50 to 100% of the surface area of the tablet core. The resulting tablets preferably have a concentration of at least 50N/cm ² 、60N/cm ² And most preferably at least 70N/cm ² Tensile strength of (c).

In one embodiment, the following coating method is applied:

first, the tablet cores are fixed (vacuum) on a turntable, charged, transported through a coating chamber, and the oppositely charged coating powder is brought into contact with the tablet core surface. The powder layered tablet cores were then transported on a rotating disc under an IR lamp and the coating melted. The tablet cores are then transferred to an adjacent second turntable, and the process is repeated for the bottom portion of the tablet cores.

Film thickness: 20-50 μm.

Typical coating weights are 3-4% of the core weight, e.g. 6mg coating on 10mm double tabs. For a 12mm round tablet core, the maximum coating weight was 20mg. The coating is preferably highly uniform and preferably has a uniform thickness.

And a heating step: this involves heating the tablet starting at room temperature so that the tablet surface temperature peaks at about 100 c and in the tablet core about 70 c, which is heated for 20 seconds. The total heat exposure is much shorter than for conventional film coatings (60 to 70 ℃ for 1 to 2 hours).

Preferably, the coating composition is non-conductive and has a melting point below 103 ℃, for example melting within 5 seconds at 130 ℃.

Preferably, the core is electrically conductive. If it is not electrically conductive, the tablet core preferably comprises 3 to 5% salt, such as NaCl, KCl, lactitol (lactilol) or citric acid.

In one embodiment, the S1P modulator provides conductivity to the tablet core.

Accordingly, the present invention provides a method of preparing a coated composition comprising an S1P modulator, the method comprising the steps of:

(a) Preparing a composition comprising an S1P modulator, e.g., an S1P agonist;

(b) Applying an electrostatic coating to the combination;

(c) The coating was fixed.

In a particularly preferred method, the S1P modifier represents at least 50%, for example at least 60%, typically more than 75% of the conductive component of the core composition.

The S1P modifier may be the only conductive component in the core composition.

The coating may also be applied by spraying techniques. Conveniently, the tablet cores may be treated prior to spraying at room temperature or by warming, for example, with warm air at 40 ℃ up to 70 ℃ up to 40 ℃. To avoid sticking of the tablet core, the spraying process is preferably stopped at certain time intervals, after which the tablet core is warmed again. It is also possible to automatically adjust the spray volume without stopping the process of spraying, for example by taking into account the temperature of the exhaust gas and/or the tablet core.

A variety of designs, prints, shapes, etc. can be applied to the coating to provide a finished product with a distinctive appearance.

The spray pressure can vary over a wide range, with satisfactory results generally being obtained with a spray pressure of about 1 to about 1.5 bar.

Composition comprising a disintegrant

Alleviating dysphagia may also be improved with the use of rapidly disintegrating dosage forms, such as rapidly disintegrating tablets.

In another aspect, the present invention provides a rapidly disintegrating solid pharmaceutical composition comprising:

(a) S1P modulators, e.g. S1P agonists

(b) Alkaline earth metal silicate

(c) Disintegrating agent

Wherein the ratio of silicate to disintegrant is 2:1 to 10:1.

Alkaline earth metal silicates include calcium silicate and magnesium silicate.

The disintegrant may also comprise an effervescent agent.

Examples of disintegrants include, but are not limited to, croscarmellose, crospovidone, and sodium starch glycolate.

The composition may further comprise a filler, which may be selected from, for example, gelatin, sugar alcohols such as mannitol, sorbitol, dextrose, sucrose, lactose, maltose, sorbitol, maltodextrin, corn syrup solids or other sugars or sugars, trehalose, polyvinylpyrrolidone, polyelectrolyte gel a chondroitin sulfate, cellulose, starch derivatives, pullulan, glycine, sodium docusate, PVC, HPC-SL, mannitol and glycerol, xanthan/carrageenan/gum arabic/guar/tragacanth, mannitol, polysorbate 60, sodium dodecyl sulfate, fatty acids, bile salts, sodium methyl hydroxy benzoate, sodium propyl hydroxy benzoate, polyols and starches.

The composition may also or alternatively comprise a lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal silica or talc.

The composition may also comprise additional binders such as PVP, for example cellulose, polyethylene glycol, polyvinylpyrrolidone, starch cement, acacia, alginic acid, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, kalto ctrin, methyl cellulose, polyethylene oxide, povidone, sodium alginate or hydrogenated vegetable oil.

The composition may also or alternatively comprise a surfactant, such as sodium lauryl sulfate or docusate sodium.

The composition may also or alternatively comprise an effervescent agent, such as sodium bicarbonate or citric acid.

The composition may also or alternatively comprise a flavouring agent.

The composition may also or alternatively comprise a glidant, such as silicon dioxide.

The composition may also or alternatively comprise a sweetener.

The composition may also or alternatively comprise a pH adjuster, such as citric acid or fumaric acid.

In one embodiment, the present invention provides a composition comprising:

0.1 to 1% S1P modulator, e.g., S1P agonist;

60 to 90% bulking agent, such as sugar alcohol;

20 to 45% silicate; and

4 to 10% of a disintegrant.

The compositions of the invention may be in the form of, for example, tablets, capsules, caplets, lozenges, pills, minitablets, pellets, beads or granules.

When the solid compositions are pellets or granules, they may be applied as such or filled into capsules, such as hard gelatin capsules, or other storage means, such as sachets, prior to administration.

The composition may be entrapped in a hydrophobic matrix which dissolves gradually or rapidly in the presence of body fluids.

The composition may further comprise a substance that swells upon contact with an aqueous liquid, and these substances may be included in the composition, including polymeric substances, selected from the group consisting of croscarmellose sodium, croshydroxypropyl cellulose, high molecular weight hydroxypropyl cellulose, carboxymethyl amide, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone, and high molecular weight polyvinyl alcohol.

Preferably, the composition has a Disintegration Time (DT) of less than 60 seconds after contact with a liquid, such as water or saliva.

It is particularly preferred that DT is about 30 seconds.

Tablet hardness may be adjusted so that any particular composition has a particular DT. In this regard, the compositions of the present invention may have different hardness.

Thus, the compositions of the present invention may have, for example, 30N/cm ² To 80N/cm ² Tensile strength between.

Preferably, upon disintegration, the composition has a particle size of 1nm to 10mm, for example 50nm to 200nm, which can dissolve or form a very fine suspension.

For fast disintegration times, the ratio of silicate, e.g. calcium silicate, to disintegrant may be 2:1 to 10:1, e.g. 3:1 to 7:1, typically 6:1, 5:1 or 4:1.

In one embodiment, the ratio of calcium silicate to disintegrant is 5:1. For example, the ratio of calcium silicate to crospovidone or croscarmellose may be 5:1.

In one embodiment, the present invention provides a capsule comprising a plurality of pellets of the present invention having a rapid disintegration rate.

Improvements in rapid disintegration or disintegration efficiency may provide higher solubility of the active substance. Higher solubility of the drug may lead to higher bioavailability and thus lower risk of precipitation in body fluids.

Bioavailability of S1P receptor modulators, particularly S1P receptor agonists, can be improved by adding sites of oral absorption to the oral absorption site, potentially leading to a reduction in first pass effects. If the S1P receptor modulator is orally absorbed via the sublingual route, oral mucosa, esophageal lining and/or tonsils, the bioavailability will be increased because the oral absorption route prevents the gastrointestinal tract (P-gp in the intestine) and the hepatic first pass effect. Increased bioavailability may allow lower doses, thereby improving safety.

Pharmaceutical dosage forms suitable for delivery of a drug to the oral cavity for oral, sublingual or gingival absorption may be employed in the presence and absence of enhancers such as, but not limited to, those described in the examples.

Examples of such dosage forms include, but are not limited to: oral sprays, effervescent tablets, granules, orally disintegrating tablets, films or wafers, and mucoadhesive discs (mucoadhesive disc) or patches.

Preferably, the dosage of the active ingredient ranges from 0 to 1000mg, for example from 0 to 500mg.

Compositions comprising lyophilized dosage forms

In another aspect, the invention provides a rapidly disintegrating pharmaceutical composition comprising a lyophilized dosage form of an S1P modulator, e.g., an S1P agonist.

In one embodiment, the composition comprises a lyophilized dosage form comprising particles of one or more S1P modulators, e.g., S1P agonists, which may be uncoated or coated with a polymer or lipid substance that exhibits minimal release of the drug in the mouth.

This can be achieved, for example, by applying coarse coated drug particles and controlling the viscosity of the suspension by reducing the temperature of the hold time in the suspension to minimize sedimentation of the particles without changing the physical properties of the drying unit.

The resulting dosage form exhibits delayed release of the drug for a period of time at least sufficient to mask the taste in the mouth prior to swallowing, and typically delayed release for a longer period of time to provide controlled or sustained release of the drug after swallowing.

The carrier material, upon lyophilization, forms a network or matrix comprising the S1P modulator, e.g., S1P agonist, which may be any water-soluble or water-dispersible material (pharmaceutically acceptable), is inert to the pharmaceutically active material, and is capable of forming a rapidly disintegrating network, i.e., disintegrates in the mouth, e.g., within 10 seconds or less.

The effect of a lyophilized dosage form is that the dosage form is highly dispersed and thus able to disintegrate rapidly. Thus, the composition may form a very fine suspension or solution upon contact with saliva in the mouth.

The preferred carrier material is gelatin, typically pharmaceutical grade gelatin. Other materials may be used as carrier materials including, for example, hydrolyzed dextrose, dextran, dextrin, maltodextrin, alginates, hydroxyethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, corn syrup solids, pectin, carrageenan, agar, chitosan, carob, xanthan, guar, gum arabic, tragacanth, konjac flower (conjac flower), rice flower, gluten, sodium starch glycolate, soy fibrin, potato protein, papain, horseradish peroxidase, glycine, and mannitol.

The composition may also comprise other excipients, which may be, for example, cellulose or sugar alcohols.

However, additional excipients which are not used as carrier substances may be used and which may be selected from, for example, sugar alcohols such as mannitol, sorbitol, dextrose, sucrose, lactose, maltose, sorbitol, maltodextrin, corn syrup solids, trehalose, polyvinylpyrrolidone, polyelectrolyte gel a chondroitin sulfate, cellulose, starch derivatives, pullulan, glycine, sodium docusate, PVC, HPC-SL, mannitol and glycerol, xanthan/carrageenan/gum arabic/guar/tragacanth, mannitol, polysorbate 60, sodium lauryl sulfate, fatty acids, bile salts, sodium methyl hydroxy benzoate, sodium propyl hydroxy benzoate, polyols and starches.

The composition may be entrapped in a hydrophilic matrix which dissolves gradually or rapidly in the presence of body fluids.

In one embodiment, the composition comprises a lyophilized dosage form of gelatin and a polysaccharide such as pullulan or sugar alcohol, an S1P receptor agonist or other modulator.

In particular embodiments, sugar alcohols are used as structure-forming agents.

In another embodiment, the gelatin and sugar alcohol are present in a ratio of 3:1 to 1:3, e.g., 2:1 to 1:2, typically 1:1.

In further embodiments, the gelatin is present in an amount of 2 to 10%, e.g., 2 to 4%, and the sugar alcohol is present in an amount of 0.1 to 15%, e.g., 0.5 to 8%.

The composition may also or alternatively comprise a binder, such as PVP, for example cellulose, polyethylene glycol, polyvinylpyrrolidone, starch cement, acacia, alginic acid, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, kalto ctrin, methyl cellulose, polyethylene oxide, povidone, sodium alginate or hydrogenated vegetable oil.

The composition may also or alternatively comprise a disintegrant (with or without an effervescent agent), such as croscarmellose sodium (croscarmellose), crospovidone, or sodium starch glycolate.

The composition may also or alternatively contain a lubricant such as stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oils such as hydrogenated castor oil (e.g., hydrogenated castor oilOr->101 Mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silica, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or mixtures of any of the foregoing.

The composition may also or alternatively comprise a surfactant, such as sodium lauryl sulfate, docusate sodium.

The composition may also or alternatively comprise a flavouring agent.

The composition may also or alternatively comprise a sweetener.

The composition may also or alternatively comprise a viscosity enhancing agent.

When the solid compositions are pellets or granules, they may be applied as such or filled into capsules, such as hard gelatin capsules or other storage means, such as sachets, prior to administration after application of the coating described below.

The diameter of the pellets and granules may be 2mm to 0.3mm, for example the size of "standard pellets" is 1 to 0.6mm and the size of "beaded pellets" is 0.4 to 0.8mm.

Rapid disintegration or higher efficiency may provide higher solubility of the active substance. Higher solubility of the drug may lead to higher bioavailability and thus lower risk of precipitation in body fluids.

The term "rapidly disintegrate" as used herein refers to a solid dosage form that disintegrates in water at 37 ℃ in 60 seconds or less. This form disintegrates typically in about 5 to 20 seconds, more typically in 5 to 10 seconds or less, when tested by a method similar to Disintegration Test for Tablets (disintegration test of tablets) described in british patent No. 1548022, b.p.1973.

Pharmaceutical dosage forms suitable for delivery of a drug to the oral cavity for oral, sublingual or gingival absorption will be employed in the presence and absence of enhancers such as, but not limited to, those described in the examples.

Examples of such dosage forms include, but are not limited to: oral sprays, effervescent tablets, granules, orally disintegrating tablets, films or wafers, and mucoadhesive discs or patches.

The dosage forms may be prepared by known methods, resulting in suspensions and the like. The liquid suspension is then poured into separate units, for example contained in a trough of a suitable mould. Alternatively, the suspension may be in the form of a solid unit, such as a frozen unit or a gel unit (in which the carrier material is susceptible to forming a gel). Typically, each unit will contain up to 250mg, for example 10 to 100mg, of drug. Unit dosage forms of rapidly disintegrating forms of the drug are included in the present invention.

The suspension of particles in the carrier material is preferably separated into units by introduction into a mold, which preferably includes a plurality of grooves, each groove having the shape and size desired for the oral dosage form product. The mould preferably comprises a plurality of grooves formed in the film material layer which may be similar to the materials commonly used in pharmaceutical blister packages.

An alternative method of forming frozen or gel units of the isolated suspension involves solidifying the mixture in the form of droplets. For example, the suspension may be passed through one or more cavities to form a spray of droplets, spheres, or small particles, which may be solidified by passing a cold gas or liquid (e.g., liquid nitrogen). Alternatively, the droplets, spheres or sprays may be solidified by contacting a chilled liquid that is immiscible with the solution or suspension and which has a density such that the droplets either fall from the immiscible liquid during solidification or float on the surface of the immiscible liquid.

The removal of the continuous phase from the isolated units of suspension comprising the pharmaceutically active substance is carried out by techniques well known to those skilled in the art. For example, when the isolated units are in liquid form, they are typically frozen or gelled prior to drying. The suspension contained in the tank suitable for the mould is frozen, for example by freezing the mould throughout a gaseous cooling medium, for example liquid nitrogen, or by inserting the mould into a nitrogen-sprayed freezer. Alternatively, the mold may be cooled by a cooling surface. Once the dosage form is frozen, the mold may be stored in a freezer compartment prior to drying.

The frozen isolated units may be dried by lyophilization according to techniques well known in the art. The continuous phase (e.g., water) sublimates under reduced pressure during the lyophilization process, which converts the solid phase solvent (ice) directly into a gaseous state. The lyophilization process is typically performed in a lyophilization chamber, typically run under vacuum of 0.1 to 1.0mBar for 180 to 500 minutes.

The invention also provides a method of preparing a pharmaceutical composition, the method comprising:

(a) Mixing a lyophilized dosage form of an S1P receptor agonist or other modulator with a structure-forming agent;

(b) Producing an aqueous suspension, wherein the aqueous suspension comprises less than 50% solids; and

(c) Optionally further freeze-drying steps are carried out.

In one embodiment, the suspension is cooled to 10 to 20 ℃, e.g. 15 ℃, prior to the lyophilization step.

Sugar alcohol-free composition

In a further aspect, the present invention provides a solid pharmaceutical composition suitable for oral administration, the composition comprising:

(a) S1P receptor modulators, e.g., S1P agonists; and

(b) The microcrystalline cellulose is a compound of cellulose,

no sugar alcohol is contained.

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 oils such as hydrogenated castor oil (e.g., hydrogenated castor oil Or (b)101 Mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silica, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or mixtures of any of the foregoing.

Preferred lubricants include magnesium stearate or hydrogenated vegetable oil.

The composition preferably comprises from 0.01 to 5% by weight, more preferably from 1 to 3% by weight, for example about 2% by weight, of lubricant based on the total weight of the composition.

The composition may comprise one or more additional excipients, such as a carrier, binder or diluent.

The composition may comprise an additional binder, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dicalcium phosphate, PVP, such as cellulose, polyethylene glycol, polyvinylpyrrolidone, starch syrup, acacia, alginic acid, carboxymethyl cellulose, hydroxyethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, kalto ctrin, methyl cellulose, polyethylene oxide, povidone, sodium alginate or hydrogenated vegetable oil.

The composition may be in the form of a powder, granule or pellet or in unit dosage form, such as a tablet or capsule. The composition is well suited for encapsulation in orally administrable capsule shells, in particular hard gelatin shells. Alternatively, the composition may be compressed into tablets.

Tablets may be coated, for example, with talc or a polysaccharide (e.g., cellulose) or hydroxypropyl methylcellulose coating.

The composition may also comprise a disintegrant. Examples of disintegrants are, for example, croscarmellose, crospovidone and sodium starch glycolate.

The composition may comprise a release rate controlling additive. For example, the drug may be entrapped in a hydrophobic polymer matrix so as to be gradually released from the matrix upon contact with body fluids.

In one embodiment, the composition comprises silica.

Microcrystalline cellulose may be used as a diluent, carrier, filler or bulking agent and may suitably beThe particle size of microcrystalline cellulose may vary.

The use of the microcrystalline cellulose composition may help promote uniform distribution of the S1P receptor modulator in the microcrystalline cellulose in the composition. Higher surface area can be achieved by providing a microcrystalline cellulose formulation comprising particles having a smaller average size and/or a coarser surface per particle.

It has also been found that the use of micronized microcrystalline cellulose (e.g., having an average particle size of 30 μm or less) improves the compressibility and hardness of tablets formed from the composition.

The composition preferably comprises microcrystalline cellulose in an amount of from 75 to 99.99% by weight, for example from 85 to 99.9%, for example from 90 to 99.5% by weight, based on the total weight of the composition.

Typically, sugar alcohols include lactose, sucrose, dextrose, mannitol, or sorbitol.

(a) S1P receptor agonists or other modulators, e.g. microcrystalline celluloseMixing;

(b) Grinding and/or granulating the mixture obtained in (a); and

(c) Optionally mixing the milled mixture obtained in (b) with a lubricant.

By applying this method, a formulation is obtained with a good level of content and mixing uniformity (i.e. a substantially uniform distribution of the S1P receptor modulator in the composition), dissolution time and stability.

S1P receptor modulators (e.g., 2-amino-2- [2- (4-octylphenyl) ethyl ]]Propane-1, 3-diol or other S1P receptor agonist, hydrochloride) is optionally micronised prior to step (a), and/or sieved, for example with a 400 to 500 μm sievePre-screening was performed to remove lumps. The mixing step (a) suitably comprises mixing the S1P receptor agonist with microcrystalline cellulose, e.gMixing in any suitable mixer or mixer, for example 100 to 400 revolutions.

The method may be carried out by dry mixing the components. In this case, the milling step (b) may suitably comprise sieving the mixture obtained in (a), preferably in the size range 400 to 500 μm. The treatment step (a) may comprise a mixing step of first mixing the total amount of S1P receptor agonist with a small amount of microcrystalline cellulose, e.gFor example, 5 to 25% by weight of the total weight of microcrystalline cellulose to form a premix. Subsequently, the remaining amount of microcrystalline cellulose, e.g. >Added to the premix. Step (a) may further comprise the step of adding a binder solution, such as methylcellulose and/or xylitol, such as an aqueous solution, to the mixture.

Alternatively, a wet granulation process is applied. In this embodiment, the S1P receptor modulator is preferably first mixed with the desired microcrystalline cellulose (e.g.) Dry mixing and then mixing the obtained microcrystalline cellulose (e.g.)>) the/S1P receptor modulator mixture is dry mixed with a binder (e.g., hydroxypropyl cellulose or hydroxypropyl methylcellulose). Then adding water and applying for exampleThe mixture was granulated by an automatic granulator. The particles are then dried and ground.

Compositions comprising a coating comprising an S1P receptor agonist

By applying a coating comprising an S1P receptor modulator to a pharmaceutical composition, different dosage strengths or combinations may be formulated.

Accordingly, in a further aspect, the present invention provides a pharmaceutical composition comprising a coating comprising an S1P receptor modulator, e.g. an S1P receptor agonist.

Pharmaceutical compositions generally comprise a tablet core coated with a coating comprising an S1P receptor modulator, e.g. an S1P receptor agonist.

The tablet core may be any solid formulation for oral administration.

The term "tablet core" in a broad sense includes not only tablets, pellets or granules, but also capsules, for example soft or hard gelatin or starch capsules. In particular, the tablet core may be a granule, a pellet, a tablet or a minitablet. Such tablet cores may be prepared in conventional manner.

In embodiments, the tablet core further comprises an S1P receptor modulator, e.g., an S1P receptor agonist. In other embodiments, the S1P receptor agonist is not present in the tablet core.

In another embodiment, the compression composition is coated after compression.

In one embodiment, the coating is applied to the outer surface of the capsule.

The core may comprise an adjuvant and an S1P modulator, e.g. an S1P agonist.

The tablet core may contain conventional tableting ingredients including diluents, disintegrants, lubricants, wetting agents, glidants, surfactants, release aids, colorants, effervescent agents, and the like.

The tablet cores may be formulated by any known formulation method known to the skilled person.

The tablet core may include, but is not limited to, fillers such as polyols, powdered mannitol, e.g., or other sugars or sugars, sugar alcohols, etc., such as lactose, sucrose, dextrose, mannitol, and starch.

The core composition may also or alternatively comprise a binder such as PVP, for example cellulose, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, starch cement, acacia, alginic acid, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropyl methyl cellulose, magnesium aluminum silicate, kalto ctrin, methyl cellulose, polyethylene oxide, povidone, sodium alginate and hydrogenated vegetable oil.

The core composition may also or alternatively comprise a disintegrant (with or without an effervescent agent), such as croscarmellose sodium (croscarmellose), crospovidone, or sodium starch glycolate.

The core composition may also or alternatively comprise a lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal silica or talc.

In one embodiment, the tablet core comprises 1.5 to 2% lubricant, such as magnesium stearate or calcium stearate.

The core composition may also or alternatively comprise a glidant, such as silicon dioxide.

The core composition may also or alternatively comprise a surfactant, such as sodium lauryl sulfate or docusate sodium.

The core composition may also or alternatively comprise a flavoring agent.

The core composition may also or alternatively comprise an effervescent agent, such as sodium bicarbonate or citric acid.

The core composition may also or alternatively comprise a sweetener.

The core composition may also or alternatively comprise a pH adjuster, such as citric acid or fumaric acid.

The core may contain a release rate controlling additive. For example, the drug may be entrapped in a hydrophobic polymer matrix so as to be gradually released from the matrix upon contact with body fluids.

Alternatively, the drug may be entrapped in a hydrophilic matrix which dissolves gradually or rapidly in the presence of body fluids. The core may comprise two or more layers having different release characteristics. These layers may be hydrophilic layers, hydrophobic layers or a mixture of hydrophilic and hydrophobic layers. Adjacent layers in the multilayer sheet core may be separated by an insoluble barrier layer or a hydrophilic separation layer. The insoluble barrier layer may be formed from a substance used to form the insoluble shell. The hydrophilic release layer may be formed of a material that is more soluble than the other layers of the tablet core so that when the release layer dissolves, the release layer of the tablet core is exposed.

The tablet core may also contain substances that swell upon contact with aqueous liquids, and these substances may be included in the composition, including polymeric substances including croscarmellose sodium, croshydroxypropyl cellulose, high molecular weight hydroxypropyl cellulose, carboxymethyl amide, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone, and high molecular weight polyvinyl alcohol.

The tablet core may contain additional pharmaceutically active ingredients in addition to the S1P modulator, e.g. S1P agonist.

In one embodiment, when the core composition is in unit dosage form, each unit dosage suitably comprises from 0.5 to 10mg of S1P receptor modulator, e.g. S1P agonist.

In one embodiment, the present invention provides a tablet core composition comprising a sugar alcohol. Examples of tablet-and-chip formulations comprising S1P receptor modulators, e.g. S1P agonists, can be found in WO 2004/089341, which describes formulations of S1P modulators with sugar alcohols.

Preferably, both the core and the coating components are micronized.

The preferred dosage range of the active ingredient is 0 to 1000mg.

The coating composition may be based on a powder or a liquid.

The coating composition may comprise a polymeric resin.

The coating composition may also or alternatively comprise a flavouring agent.

The composition may comprise one or more other coatings. The composition may be separated from the drug-containing coating by a protective coating. Alternatively or additionally, the drug-containing coating may be overcoated. The or each further coating may comprise a polymeric material, such as hydroxypropyl methylcellulose or hydroxypropyl cellulose. Such coatings may be prepared and applied in compositions using techniques known in the art.

The present invention also provides a method of preparing a coated pharmaceutical composition, the method comprising:

(a) Preparing a tablet core composition; and

(b) The tablet cores are coated with a coating comprising an S1P receptor modulator.

The core composition may be prepared using any of the techniques described herein.

The coating is applied to the tablet core using techniques well known in the art, such as by fluid bed treatment.

S1P modulators

Each of the different compositions described herein comprises an S1P modulator. In an embodiment of each of the compositions described herein, the S1P modulator is an S1P agonist.

S1P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1, 3-diol or 2-amino-propanol derivatives. Examples of suitable S1P receptor agonists are, for example:

Compounds disclosed in EP 627406A1, e.g. compounds of formula I or pharmaceutically acceptable salts thereof

Wherein the method comprises the steps of

R ₁ Is straight-chain-or branched (C) _12-22 ) A carbon chain is arranged on the inner side of the cylinder,

which may have a bond or heteroatom in the chain selected from double, triple, O, S, NR ₆ Wherein R is ₆ Is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl; and/or

Which may have, as substituents, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or (b)

R ₁ Is phenylalkyl, wherein alkyl is straight-chain or branched (C _6-20 ) A carbon chain; or (b)

Phenylalkyl wherein alkyl is straight-or branched (C _1-30 ) A carbon chain in which said phenylalkyl group is substituted with

Optionally halogen-substituted straight-or branched (C) _6-20 ) A carbon chain is arranged on the inner side of the cylinder,

optionally halogen-substituted straight-or branched (C) _6-20 ) An alkoxy group, a chain of an alkoxy group,

straight-chain-or branched (C) _6-20 ) Alkenyloxy;

phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl;

Is straight-chain-or branched (C) _6-20 ) Alkyl chain substituted cycloalkylalkyl;

is straight-chain-or branched (C) _6-20 ) Alkyl chain substituted heteroarylalkyl;

heterocycloalkyl, wherein said alkyl is straight-or branched (C _6-20 ) A carbon chain; or (b)

Is straight-chain-or branched (C) _2-20 ) An alkyl chain-substituted heterocycloalkyl group,

and wherein the alkyl moiety in the carbon chain may have a bond or heteroatom selected from double bond, triple bond, O, S, sulfinyl, sulfonyl or NR ₆ Wherein R is ₆ As defined above;

and may have, as a substituent, an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aralkyloxy group, an acyl group, an alkylamino group, an alkylthio group, an acylamino group, an alkoxycarbonyl group, an alkoxycarbonylamino group, an acyloxy group, an alkylcarbamoyl group, a nitro group, a halogen group, an amino group, a hydroxyl group or a carboxyl group; and is also provided with

Each R ₂ 、R ₃ 、R ₄ And R is ₅ H, C independently _1-4 Alkyl or acyl;

compounds disclosed in EP 1002792A, e.g. compounds of formula II or pharmaceutically acceptable salts thereof

Wherein the method comprises the steps of

m is 1 to 9; and is also provided with

Each R ₂ 、R ₃ 、R ₄ And R is ₅ Independently is H, alkyl or acyl;

compounds disclosed in EP 0778263A1, e.g. compounds of formula III or pharmaceutically acceptable salts thereof

Wherein the method comprises the steps of

W is H; straight or branched chain (C) _1-6 ) Alkyl, (C) _2-6 ) Alkenyl or (C) _2-6 ) Alkynyl; phenyl unsubstituted or substituted by OH; r is R ₄ O(CH ₂ ) _n The method comprises the steps of carrying out a first treatment on the surface of the Or a straight chain or branched chain substituted with 1 to 3 groups selected from (C _1-6 ) Alkyl: halogen, cycloalkyl, phenyl or phenyl substituted by OH;

x is H or an unsubstituted or substituted linear alkyl group having p carbon atoms or an unsubstituted or substituted linear alkoxy group having (p-1) carbon atoms, for example substituted with 1 to 3 substituents selected from the group consisting of: alkyl, OH, alkoxy, acyloxy, amino, alkylamino, acylamino, oxo, haloalkyl, halogen, unsubstituted phenyl or phenyl substituted with 1 to 3 substituents selected from alkyl, OH, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, haloalkyl and halogen;

y is H, alkyl, OH, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, haloalkyl or halogen, Z is a single bond or a linear alkylene having q carbon atoms,

each p and q is independently an integer from 1 to 20, provided that 6.ltoreq.p+q.ltoreq.23, m is 1, 2 or 3,

n is either 2 or 3 and the number of n is,

each R ₁ 、R ₂ 、R ₃ And R is ₄ Independently is H, alkyl or acyl.

Compounds disclosed in WO 02/18395, e.g. of formula IVa or IVb or pharmaceutically acceptable salts or hydrates thereof

/>

Wherein the method comprises the steps of

X is O, S, NR ₁ Or a group- (CH) ₂ ) _n -the group is unsubstituted or substituted with 1 to 4 halogens;

n is 1 or 2 and is preferably 1 or 2,

R ₁ is H or (C) _1-4 ) Alkyl, which alkyl is unsubstituted or substituted by halogen;

R _1a h, OH, (C) _1-4 ) Alkyl or O (C) _1-4 ) Alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens;

R _1b is H, OH or (C) _1-4 ) Alkyl, wherein alkyl is unsubstituted or substituted with halogen;

each R ₂ Independently selected from H or (C) _1-4 ) Alkyl, which alkyl is unsubstituted or substituted by halogen;

in the case of compounds of formula IVa, R ₃ Is H, OH, halogen or O (C) _1-4 ) Alkyl, wherein alkyl is unsubstituted or substituted with halogen;

in the case of compounds of formula IVb, R ₃ H, OH is a,Halogen, (C) _1-4 ) Alkyl, wherein alkyl is unsubstituted or substituted by hydroxy, or O (C _1-4 ) Alkyl, wherein alkyl is unsubstituted or substituted with halogen;

y is-CH ₂ -, -C (O) -, -CH (OH) -, C (=noh) -, O or S,

R ₄ is (C) _4-14 ) Alkyl or (C) _4-14 ) Alkenyl groups;

compounds disclosed in WO 02/06268 or JP-14316985, e.g. compounds of formula VII or pharmaceutically acceptable salts or esters thereof

Wherein the method comprises the steps of

Each R ₁ And R is ₂ Independently is H or an amino protecting group;

R ₃ is hydrogen or a hydroxyl protecting group;

R ₄ is (C) _1-6 ) An alkyl group;

n is an integer from 1 to 6;

x is ethylene, vinylene, ethynylene, of formula-D-CH ₂ -a group (wherein D is carbonyl), a group having the formula-CH (OH) -, O, S or N; aryl or aryl substituted with three groups a selected from the group defined below;

y is a single bond, C _1-10 Alkylene, C substituted with one to three substituents selected from the group consisting of groups a and b _1-10 Alkylene, C with O or S in the middle or at the end of the carbon chain _1-10 Alkylene, or C with O or S in the middle or end of the carbon chain _1-10 An alkylene group substituted with one to three substituents selected from the group consisting of groups a and b;

R ₅ is hydrogen, cycloalkyl, aryl, heterocyclic, cycloalkyl substituted with one to three groups selected from groups a and b, aryl substituted with one to three groups selected from groups a and b, or heterocyclic substituted with one to three groups selected from groups a and b; and is also provided with

Each R ₆ And R is ₇ Independently is H or a substituent selected from group a;

the < group a > is halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxyl, lower aliphatic acyl, amino, mono-lower alkylamino, di-lower alkylamino, lower aliphatic acylamino, cyano and nitro;

< group b > is cycloalkyl, aryl, heterocycle, each optionally substituted with up to three substituents selected from group a;

provided that when R ₅ When hydrogen is provided, Y is a single bond or linear C _1-10 An alkylene group,

for example (2R) -2-amino-4- [3- (4-cyclohexyloxybutyl) benzo [ b ] thiophen-6-yl ] -2-methylbutan-1-ol.

When in the compounds of formula I, the carbon chain is taken as R ₁ Is substituted, preferably by halogen, nitro, amino, hydroxy or carboxyl. When the carbon chain is interrupted by an optionally substituted phenylene group, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted with halogen, nitro, amino, methoxy, hydroxy or carboxyl. Acyl may be a residue R-CO-wherein R is C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl or phenyl-C _1-4 An alkyl group.

Preferred compounds of formula I are those wherein R ₁ Is linear or branched, preferably linear alkyl having from 13 to 20 carbon atoms, which is optionally substituted by nitro, halogen, amino, hydroxy or carboxyl, and more preferably those compounds of formula I wherein R ₁ Is straight-chain or branched C _6-14 Phenylalkyl substituted with an alkyl chain (optionally substituted by halogen) and the alkyl moiety is C optionally substituted by hydroxy _1-6 Compounds of formula I which are alkyl. More preferably, R ₁ Is straight-chain or branched, preferably straight-chain C, on phenyl _6-14 phenyl-C substituted with alkyl chain _1-6 An alkyl group. C (C) _6-14 The alkyl chain may be ortho, meta or para, preferably in para.

Preferably each R ₂ To R ₅ Is H.

A preferred compound of formula I is 2-amino-2-tetradecyl-1, 3-propanediol. Particularly preferred S1P receptor agonists of formula I are 2-amino-2- [2- (4-octylphenylethyl) ] propane-1, 3-diol (hereinafter referred to as compound A) in free form or in pharmaceutically acceptable salt form, e.g. as the hydrochloride salt, i.e. FTY720, as shown below:

preferred compounds of formula II are those wherein each R ₂ To R ₅ Compounds of formula II where H and m is 4, i.e. 2-amino-2- {2- [4- (1-oxo-5-phenylpentyl) phenyl in free form or in pharmaceutically acceptable salt form (e.g. hydrochloride)]Ethyl } propane-1, 3-diol (hereinafter referred to as compound B).

Preferred compounds of formula IVa are the compound A-phosphates (R ₂ Is H, R ₃ Is OH, X is O, R _1a And R is _1b Is OH). Preferred compounds of the formula V are the compounds B-phosphates (R ₁ Is CH ₂ OH，R ₃ Is H, X is O, m is 1, R ₂ Is a phosphate and R is 2- [4- (1-oxo-5-phenylpentyl) phenyl ]]Ethyl).

When the compounds of formulas I through VII have one or more asymmetric centers in the molecule, various optical isomers as well as racemates, diastereomers and mixtures thereof are included.

Examples of pharmaceutically acceptable salts of the compounds of formulae I to VII include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, maleate, mesylate and besylate, or, where appropriate, salts with metals, such as sodium, potassium, calcium and aluminum salts, salts with amines, such as triethylamine, and salts with amino diacids, such as lysine. The compounds and salts of the invention include both hydrate and solvate forms.

The compositions of the present invention may comprise salts and/or free acids of one or more S1P modulators.

The compositions of the present invention preferably comprise from 0.01 to 20% by weight, more preferably from 0.1 to 10%, for example from 0.5 to 5% by weight of S1P receptor modulator, based on the total weight of the composition.

When the pharmaceutical capsule is a unit dosage form, each unit dosage may suitably contain from 0.5 to 10mg of the s1p receptor modulator.

Use of the same

The pharmaceutical compositions of the invention are used alone or in combination with other active agents for the treatment or prophylaxis of disorders, such as disclosed in US 5,604,229, WO 97/24112, WO 01/01978, US 6,004,565, US 6,274,629 and JP-14316985, the contents of which are incorporated herein by reference.

The compositions described herein may facilitate the absorption and distribution of S1P modulators across the blood brain barrier and into the brain.

In particular, the pharmaceutical composition is for:

a) Treatment and prevention of organ or tissue graft rejection, for example, for treating recipients of heart, lung, heart-lung combinations, liver, kidney, pancreas, skin or cornea transplants, and for preventing graft versus host disease, such as occurs after sometimes bone marrow transplantation; in particular for the treatment of acute or chronic allograft and xenograft rejection or the transplantation of insulin-producing cells (e.g. islet cells);

b) Treating and preventing autoimmune diseases or inflammatory disorders, such as multiple sclerosis, arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, hepatitis, and the like;

c) Treating and preventing viral myocarditis and viral diseases caused by viral myocarditis, including hepatitis and AIDS.

In one embodiment, the invention relates to the treatment of inflammatory disorders. In one example, the invention relates to a composition for controlling and/or inhibiting mast cell activation and secretion for use in alleviating inflammatory conditions, e.g. in the brain, such as in multiple sclerosis.

The invention also provides a method of protecting a multiple sclerosis subject against neurodegenerative brain inflammation comprising administering to the subject a composition described herein, e.g., a composition comprising an S1P agonist or other modulator.

The compositions of the present invention, as well as any concentrates and pharmaceutical solutions prepared therefrom for dilution, may be administered in a therapeutically effective amount against a disease or condition that may be treated by administration of S1P receptor modulators.

The exact amount of S1P receptor modulator, or a pharmaceutically acceptable salt thereof, to be administered to a subject can vary widely. The dosage may depend on the particular compound, the route of administration, the rate of administration, the strength of the particular concentrate or drug solution used, the nature of the disease or disorder being treated, and the sex, age and weight of the patient. The dosage may also depend on the presence, nature and extent of any side effects that may accompany the administration of the concentrate or pharmaceutical formulation. Typically, a dose of 0.5 to 5mg of S1P receptor modulator, e.g. compound a, is administered to a child.

The compositions of the invention and any concentrates used for dilution, as well as the respective pharmaceutical solutions, may be used in combination with other immunosuppressants, steroids (e.g., prednisolone, methylprednisolone, dexamethasone, hydrocortisone, etc.), or non-steroidal anti-inflammatory drugs. The combined administration of the active agents may be simultaneous or sequential, with any one agent administered first. The dosage of the active agents for combination therapy may depend on the efficacy and site of action of each active agent, as well as the synergy between the drugs used for combination therapy.

Detailed Description

The invention will now be described with reference to the following specific examples.

Example 1

The micronized compound 2-amino-2- [2- (4-octylphenyl) ethyl ] propane-1, 3-diol, hydrochloride (FTY 720) is sifted and mixed with a microcrystalline cellulose agent, for example Avicel PH 102. The mixture was then ground with a 30 mesh screen on a Frewitt MGI instrument (Key International inc. The magnesium stearate was sieved with a 20 mesh screen and mixed with the FTY 720/cellulose mixture. The cross-linked carboxymethyl cellulose is mixed to produce a product composition.

Examples of 6mm round, 80mg tablet cores obtained by direct compression are shown below:

composition of the components	mg/dose
		FTY720HCl	1.40
Microcrystalline cellulose, e.g. Avicel PH 102	73.80
		Magnesium stearate	0.80
Cross-linked carboxymethyl cellulose	4.00

Alternatively, the tablet core composition may be compressed on a tablet press with a 7mm die to form a 120mg tablet, examples of which may be:

composition of the components	mg/dose
		FTY720HCl	1.40
Mannitol M200	116.20
		Magnesium stearate	2.40

1mg of FTY720 in free form corresponds to 1.12mg FTY720 HCl salt.

Example 2

In a further example, the process of example 1 is repeated, except that magnesium stearate is used(hydrogenated castor oil) instead.

Example 3

In a further example, tablets were prepared as described in examples 1 and 2, except that FTY720 was replaced in each case with 2-amino-2- {2- [4- (1-oxo-5-phenylpentyl) phenyl ] ethyl } propane-1, 3-diol hydrochloride.

Examples 4 to 7

Tablets were prepared containing the following ingredients (in mg):

* The amount of xylitol shown in brackets was used as binder.

FTY720, D-mannitol and xylitol were placed in a fluid bed granulator (MP-01 model, powrex), mixed for 5 minutes, and granulated with a spray of binder solution, followed by drying until the exhaust temperature reached 40 ℃. The granulation conditions are shown below. The dried powder was passed through a 24 mesh screen, added to a specific amount of filler and lubricant, and mixed in a Mixer (WAB) for 3 minutes to prepare a powder for compaction.

The resulting powder was compressed by a tablet press (Cleanpress correct 12HUK,Kikushui Seisakusho) using a 7mm i.d. x 7.5mm R die at a pressure of 9800N.

Granulating conditions:

example 8

Examples of powder coating compositions:

the components are pre-mixed under high shear and then wet granulated by mixing with water under high shear. The granulation mixture is dried in a fluid bed dryer to reduce the moisture content to less than 3% by weight. The dried granules are ground and micronised into a powder.

Composition of the components	Composition (% w/w)
		Ammonium methacrylate copolymers, e.g. Eudragit RS	46.5
Hydroxypropyl cellulose, e.g. Klucel	28.0
		Titanium dioxide	15.0
Aluminum lake	5.0
		Polyethylene glycol 6000	5.0
Colloidal silica, e.g. Aerosil 200	0.5

Example 9:

examples of powder coating compositions:

composition of the components	Composition (% w/w)
		Ammonium methacrylate copolymers, e.g. Eudragit RS	39.75
Hydroxypropyl cellulose, e.g. Klucel	39.75
		Titanium dioxide	15.0
Aluminum lake	5.0
		Colloidal silica, e.g. Aerosil 200	0.5

Example 10:

examples of liquid coating compositions (aqueous dispersions):

in the molten or dry state, energy is transferred to the tablet core surface to melt the powder or dry the liquid and provide a uniform coating on the exposed surface of the tablet core. The energy is provided by concentrated radiation, preferably in the infrared region; the energy power demand will be determined mainly by the coating substance. After melting or drying, the coating is placed and cooled using a blower.

Composition of the components	Composition (% w/w)
		Hydroxypropyl methylcellulose	70
Glycerol	7
		Iron oxide yellow	23

Example 10

Examples of 7mm round, 127mg tablets for rapid disintegration according to the invention:

composition of the components	mg/dose
		FTY720HCl	0.56
Directly compressible mannitol, e.g. Parteck M200	82.54
		Calcium silicate	36.00
Magnesium stearate	0.90
		Crosslinked povidone	7.00

The tablets may be prepared by known methods. For example, tablets may be prepared by mixing all ingredients and further compressing into tablets and/or granulating and/or micronizing and further compressing the granules into tablets.

Example 11

A rapidly disintegrating formulation was prepared comprising gelatin (3%), mannitol (1-5%) as a structure former, sweetener, flavoring agent.

Gelatin and mannitol were added to water and heated to 40 ℃ to dissolve. The gelatin/mannitol solution is cooled to 23 ℃ and mixed with the active ingredient, e.g., S1P agonist or other modulator. The total solids content was less than 50%. The suspension was cooled to 15 ℃ first to prevent sedimentation of the suspension (coated or uncoated) before lyophilization began.

Example 12

As in example 11, except that mannitol was replaced with sorbitol.

Example 13

Example 14

Micronized compound a, e.g. 2-amino-2- [2- (4-octylphenyl) ethyl ] propane-1, 3-diol, hydrochloride (FTY 720) was sieved and 116.7g of the sieved compound was mixed with 9683.3g of microcrystalline cellulose. The mixture was then ground with a 30 mesh screen on a Frewitt MGI instrument (Key International inc. Magnesium stearate is sieved with a 20 mesh sieve and 200g of the sieved compound is mixed with the FTY720 mixture to produce a product composition.

The product composition was then compressed on a tablet press using a 7mm die to form 120mg tablets, each tablet comprising:

*1mg of Compound A in free form corresponds to 1.12mg of FTY720.

Example 15

In a further embodiment, the process of example 14 is repeated, except that magnesium stearate is used(hydrogenated castor oil) instead.

Example 16

Compound a (e.g. FTY 720) and microcrystalline cellulose (e.g. Avicel PH 102) were each sieved with an 18 mesh sieve. 1.9g of sieved FTY720 was mixed with 40g of sieved microcrystalline cellulose agent in a 32rpm stirrer for 120 revolutions. The FTY720 mixture was then sieved through a 35 mesh sieve.

The sieved FTY720 mixture was added to the granulator together with another 340.1g of microcrystalline cellulose (e.g. Avicel PH 102) and 12g of hydroxypropyl cellulose. The mixture was mixed for 3 minutes. Water was then added at a rate of 100 mL/min and the mixture was granulated for 2 min. The pellets were transferred to a tray dryer and dried at 50 ℃ for 150 minutes.

The mixture was then ground using a 35 mesh screen in a Frewitt MGI apparatus. The magnesium stearate is sieved and 6g of the sieved mixture is mixed with the FTY720 mixture at 32rpm for 90 revolutions to produce a product composition that exhibits a substantially uniform distribution of the S1P receptor agonist in the microcrystalline cellulose (e.g., avicel PH 102) in the mixture.

The product composition was then filled into size 3 hard gelatin shells on an H & K400 encapsulation apparatus. 120mg of the product composition was added to each capsule. Thus, each capsule comprises:

example 17

In a further embodiment, the process of example 16 is repeated, except that magnesium stearate is used(hydrogenated castor oil) instead.

Example 18

In a further example, the method of example 16 was repeated except that hydroxypropyl cellulose was replaced with hydroxypropyl methylcellulose.

Example 19

The micronized compound a (e.g. FTY 720) was sieved with a 425 μm (40 mesh) sieve. 58.35g of the sieved compound are mixed 240 revolutions with 4841.65g of microcrystalline cellulose (e.g. Avicel PH 102) in a 25L Bohle bin mixer. The mixture was then milled in a Frewitt MGI apparatus using a 425 μm screen and the milled mixture was mixed once more. Magnesium stearate is sieved and 100g of the sieved compound is mixed with the FTY720 mixture to produce a product composition that exhibits a substantially uniform distribution of S1P receptor agonist in the mixture.

examples 20 and 21

In a further example, capsules were prepared as described in example 19, except that each capsule contained the following amounts of each component:

examples 22 to 24

In a further example, capsules were prepared as described in examples 19 to 21, except that magnesium stearate was used in each case(hydrogenated castor oil) instead.

Examples 25 to 35

In a further example, capsules or tablets were prepared as described in examples 13 to 23, except that FTY720 was replaced in each case with 2-amino-2- {2- [4- (1-oxo-5-phenylpentyl) phenyl ] ethyl } propane-1, 3-diol hydrochloride.

Examples 36 to 38

A pharmaceutical composition comprising the following ingredients was prepared:

FTY720 and microcrystalline cellulose (e.g., avicel PH 102) at a weight ratio equal to twice that of FTY720 were mixed in a model Microspeed Mixer MS-5 (Palmer, USA) for 2 minutes at 1200 rpm. The remaining amount of microcrystalline cellulose was added to the mixture and mixed for an additional 2 minutes. 80 or 60 ml of 5% methylcellulose SM-25 solution was added from the funnel and granulated under the same conditions. The mixture was extruded from a 0.4mm mesh screen using an RG-5 extruder. The extruded material was dried at 65 ℃ through a fluid bed granulator, model STREA I (pateon, canada) and then sieved through a 24 mesh sieve. Fine particles passing through a 60 mesh sieve were removed. The obtained fine particles were filled into capsules by a Zuma capsule filling machine (100 mg/capsule).

Example 39

Examples of tablet formulations comprising 1.25mg fty720 obtainable by wet granulation.

Composition for wet granulation:

composition of the components	mg/tablet	％
			FTY HCl	1.49	1.49
HPMC 3cps	3.00	3.00
			Water granulating liquid	Proper amount of	Proper amount of
Mannitol (mannitol)	46.25	46.25
			Avicel PH 101	46.25	46.25
Aerosil 200	3.01	3.01
			Cross-linked carboxymethyl cellulose	5.00	5.00
Magnesium stearate	1.00	1.00
			Totals to	100.00	100.00

Microcrystalline cellulose was wet granulated with an aqueous solution of FTY720 and HPMC. After drying, the mixture was sieved and mixed with mannitol, silica, croscarmellose and magnesium stearate and compressed into 100mg of 6mm round tablets.

Alternatively, the formulation may be prepared in the absence of sugar alcohols (e.g., mannitol), using microcrystalline cellulose instead:

example 40

Examples of coating compositions comprising FTY 720.

Composition for coating pellets, mini-tablets and minitablets

Composition of the components	mg/tablet	％
			HPMC 3cps	1.62	11.60
FTY HCl	0.04	0.25
			Butyl hydroxy toluene	0.01	0.05
Citric acid triethyl ester	0.07	0.50
			Acetone (acetone)	6.12	43.81
Ethanol	6.12	43.81
			Total dry matter	1.74	12.39
Totals to	100.00	100.00

The polymer HPMC may also be replaced by, for example, HPC or other comparable polymers. FTY720 coating may be applied to active or placebo pellets, mini-tablets or minitablets, separated with, for example, a protective coating (e.g., HPMC) and/or covered with an outer coating (e.g., HPMC). The dosage form may be filled into capsules (e.g. HPMC or HGC) or strip packs and it is therefore possible to prepare different dosage strengths or combinations in a sense.

Claims

1. An oral pharmaceutical composition comprising an S1P receptor modulator, wherein the composition comprises a coating comprising:

(a) One or more polymer resins

(b) One or more metal oxides.

2. The composition of claim 1, wherein the one or more polymer resins comprise methacrylic acid copolymers.

3. The composition of claim 1 or claim 2, wherein the one or more polymer resins comprise cellulose.

4. The composition of any of the preceding claims, further comprising;

(c) Polyethylene glycol or sugar alcohol.

5. The composition of any of the preceding claims, further comprising;

(d) Colloidal silica.

6. The composition of any of the preceding claims comprising an ammonium methacrylate copolymer in an amount of from 35 to 50% w/w.

7. The composition of any of the preceding claims comprising hydroxypropyl cellulose in an amount of 25 to 45% w/w.

8. The composition of any of the preceding claims wherein the one or more metal oxides are present in an amount of 15 to 25% w/w.

9. The composition of any of the preceding claims comprising titanium dioxide in an amount of from 12.5 to 17.5% w/w.

10. The composition of any of the preceding claims comprising aluminum lakes in an amount of 2.5 to 7.5% w/w.

11. The composition of any of the preceding claims comprising polyethylene glycol in an amount of 0.01 to 10% w/w.

12. A composition according to any one of the preceding claims comprising colloidal silica in an amount of 0.01 to 1% w/w.

13. The composition of any of the preceding claims, wherein the coating comprises:

14. the composition of any one of claims 1 to 12, wherein the coating comprises:

composition of the components Composition (% w/w) Ammonium methacrylate copolymers, e.g. Eudragit RS 39.75 Hydroxypropyl cellulose, e.g. Klucel 39.75 Titanium dioxide 15.0 Aluminum lake 5.0 Colloidal silica, e.g. Aerosil 0.5

。

15. The composition of claim 1 comprising a liquid coating, said coating comprising:

(a) Hydroxypropyl methylcellulose

(b) Glycerol

(c) A metal oxide.

16. The composition of claim 15 wherein hydroxypropyl methylcellulose is present in an amount of 60 to 80% w/w.

17. The composition of claim 15 or 16, wherein glycerol is present in an amount of 4 to 10% w/w.

18. The composition of any one of claims 15 to 17 wherein the metal oxide is present in an amount of 15 to 30% w/w.

19. The composition of any one of claims 15 to 18 wherein the metal oxide is yellow iron oxide.

20. The composition of any one of claims 15 to 19, wherein the coating comprises:

21. A rapidly disintegrating solid pharmaceutical composition comprising:

(a) S1P receptor modulators

(b) Alkaline earth metal silicate

(c) Disintegrating agent

Wherein the ratio of silicate to disintegrant is 2:1 to 10:1.

22. The composition of claim 21, wherein the ratio is 3:1 to 7:1.

23. The composition of claim 22, wherein the ratio is 5:1.

24. The composition of claims 21 to 23 wherein the disintegrant is selected from the group consisting of crospovidone and croscarmellose.

25. The composition of any one of claims 21 to 24, wherein the disintegration time is less than 60 seconds.

26. A rapidly disintegrating pharmaceutical composition comprising a lyophilized dosage form of an S1P receptor modulator.

27. The composition of claim 26, further comprising one or more of gelatin, mannitol, sorbitol, dextrose, sucrose, lactose, maltose, maltodextrin, corn syrup solids, trehalose, polyvinylpyrrolidone, polyelectrolyte gel a chondroitin sulfate, cellulose, starch derivatives, pullulan, glycine, sodium docusate, PVC, HPC-SL, mannitol and glycerol, xanthan/carrageenan/gum arabic/gum tragacanth, mannitol, polysorbate 60, sodium lauryl sulfate, fatty acids, bile salts, sodium methyl hydroxy benzoate, sodium propyl hydroxy benzoate, viscosity enhancers, flavoring agents, sweeteners.

28. The composition of claim 26 or claim 27, wherein the disintegration time is less than 10 seconds.

29. A solid pharmaceutical composition suitable for oral administration, the pharmaceutical composition comprising:

(a) S1P receptor modulators; and

(b) Microcrystalline cellulose

No sugar alcohol is contained.

30. The composition of claim 29 comprising 90 to 99.5% by weight microcrystalline cellulose.

31. The composition of claim 29 or claim 30, wherein the microcrystalline cellulose comprises

32. A pharmaceutical composition comprising a coating, said coating comprising an S1P receptor modulator.

33. The composition of claim 32, wherein the composition comprises a tablet core coated with said coating.

34. The composition of claim 33, wherein the tablet core comprises a granule, a pellet, a tablet, or a minitablet.

35. The composition of claim 33 or claim 34, wherein the core comprises an S1P receptor modulator.

36. The composition of any one of claims 32 to 35, wherein the coating further comprises a polymer.

37. The composition of claim 36, wherein the polymer comprises cellulose.

38. The composition of claim 37, wherein the polymer comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, or methylcellulose.

39. The composition of any one of claims 32 to 38, comprising one or both of ethanol and acetone.

40. The composition of any one of claims 32 to 39, wherein the coating comprises:

composition of the components ％ Hydroxypropyl methylcellulose (HPMC) 11.60 S1P receptor modulators, e.g. FTY HCl 0.25 Butyl hydroxy toluene 0.05 Citric acid triethyl ester 0.50 Acetone (acetone) 43.81 Ethanol 43.81

。

41. The composition of any one of claims 32 to 40, wherein the composition comprises one or more additional coatings.

42. The composition of any of the preceding claims, which is in particulate form.

43. The composition of any one of claims 1 to 41 in the form of a tablet.

44. The composition of any one of claims 1 to 41 in the form of a capsule.

45. The composition of any of the preceding claims, further comprising a lubricant.

46. The composition of claim 45 wherein the lubricant comprises magnesium stearate.

47. The composition of claim 45 or claim 46 comprising 1.5 to 2.5% by weight of lubricant.

48. The composition of any of the preceding claims comprising cellulose selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or methylcellulose.

49. The composition of claim 29, which is in the form of a hard gelatin capsule comprising the S1P receptor modulator and microcrystalline cellulose, free of sugar alcohols.

50. A composition according to any one of the preceding claims comprising 0.5 to 5% by weight of S1P receptor modulator.

51. The composition of any of the preceding claims, wherein the S1P receptor modulator is an S1P receptor agonist.

52. The composition of claim 51, wherein the S1P receptor agonist comprises 2-amino-2- [2- (4-octylphenyl) ethyl ] propane-1, 3-diol or 2-amino-2- {2- [4- (1-oxo-5-phenylpentyl) -phenyl ] ethyl } propane-1, 3-diol or a pharmaceutically acceptable salt thereof.

53. A method of treating an individual in need of immunosuppression, the method comprising administering to the individual a composition of any preceding claim.

54. Use of a composition according to any one of claims 1 to 52 for the manufacture of a medicament for the prevention or treatment of organ or tissue graft rejection or for the prevention or treatment of inflammatory or autoimmune diseases.

55. Use of a composition according to any one of claims 1 to 52 for the prevention or treatment of organ or tissue graft rejection or for the prevention or treatment of inflammatory or autoimmune diseases.

56. A method of protecting a multiple sclerosis subject against neurodegenerative brain inflammation, the method comprising administering to the subject a composition according to any one of claims 1 to 52.

57. A method of preparing a coated pharmaceutical tablet for oral administration, the method comprising:

(a) Preparing a core tablet comprising an S1P receptor modulator; and

(b) Use of a coating as defined in any one of claims 1 to 20.

58. A method of preparing a pharmaceutical composition, the method comprising:

(a) Mixing a lyophilized dosage form of an S1P receptor modulator with a structure forming agent;

(b) Preparing an aqueous suspension, wherein the aqueous suspension comprises less than 50% solids; and

(c) Optionally further freeze-drying steps are carried out.

59. A method of preparing the pharmaceutical composition of claim 29, the method comprising the steps of:

(a) Contacting an S1P receptor modulator with microcrystalline cellulose, e.gMixing;

(b) Grinding the mixture obtained in (a); and

(c) Mixing the milled mixture obtained in (b) with a lubricant.

60. A method of preparing the pharmaceutical composition of claim 32, the method comprising:

(a) Preparing a tablet core composition;