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1. (WO2013091704) PHARMACEUTICAL COMPOSITION COMPRISING FINGOLIMOD
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PHARMACEUTICAL COMPOSITION COMPRISING FINGOLIMOD

The invention relates to pharmaceutical compositions comprising the compound Fingolimod as the active ingredient.

BACKGROUND OF THE INVENTION

Fingolimod (often coded as FTY 720), chemically 2-amino-2-[2-(4-octylphenyl)ethyl]-propane-l,3-diol of the formula (1)


is a pharmaceutically active immunomodulating compound. It is a structural analogue of sphingosine and its pharmaceutical activity is associated with its modulating activity towards sphingosine- 1 -phosphate (SIP) receptors.

In 2010, Fingolimod became the first oral disease-modifying drug approved for treating multiple sclerosis.

Fingolimod itself is a prodrug and gets phosphorylated to the active metabolite (S)-Fingolimod phosphate ester by sphingosine kinases in liver cells.

Fingolimod may form stable acid addition salts, of which Fingolimod hydrochloride is the most common one.

The approved product sold, e.g., under trade name Gilenya, is a hard-shell capsule filled by a powder comprising 0.56 mg of Fingolimod hydrochloride (corresponding to 0.5 mg of Fingolimod) per capsule. In further the powder comprises mannitol as a filler and small amount of magnesium stearate as lubricant.

Fingolimod has been first disclosed in EP 627 406 of Yoshitomi, where also two basic routes for making it have been described.

Various powderized pharmaceutical compositions comprising Fingolimod, which may serve for purposes of oral administration of Fingolimod to a patient in need thereof, have been disclosed in prior art documents.

Thus, WO 2004/089341 discloses a solid pharmaceutical composition suitable for oral administration comprising various SIP receptor agonists and a sugar alcohol. The sugar alcohol may act as a diluent, carrier, filler or bulking agent and may suitably be mannitol, maltitol, inositol, xylitol and/or lactitol. It is taught that these compositions do not suffer from the disadvantages of liquid formulations for injections or oral use and have good

physicochemical and storage properties. In particular, the compositions show a high level of content uniformity as well as high stability.

The composition may be in a form of a powder, granule, pellet or a tablet.

In examples of preferred embodiment, Fingolimod hydrochloride is mixed with mannitol and lubricant and, optionally with a binder such as UPC or HPMC, milled and/or granulated.

Apparently, the composition of the marketed product Gilenya falls within the compositions disclosed in WO 2004/089341.

WO 2008/037421 provides formulations comprising SIP receptor modulator and adapted for oral administration in solid form, which can be easily swallowed, e.g. by children or elderly patients. The invention provides dosage forms, which disintegrate rapidly in the mouth and do not depend on the presence of taste masking agent or on presence of water for washing down the dosage forms. It also provides compositions comprising an SIP receptor modulator, wherein the composition is coated by a coating comprising one or more polymer resins and one or more metal oxides. In further, it provides a composition comprising an SIP receptor modulator and microcrystalline cellulose in the absence of a sugar alcohol.

WO 2009/048993 teaches that various SIP receptor modulators comprising an aminopropane-l,3-diol group (such as, e.g., Fingolimod) are not easy to formulate in a solid oral formulation; only a limited number of excipients are potentially feasible with such amino diols . In particular, reducing sugars are not considered suitable due to danger of Maillard reaction with the amino-group. Thus, according to WO 2009/048993 , the only suitable fillers providing stable blends with the aminopropane-l-3-diol based SIP receptor modulator are lactose, lactose monohydrate, maize starch, mannitol, xylitol, sorbitol, sucrose,

microcrystalline cellulose, dibasic calcium phosphate, maltodextrin and gelatin. This selection was supported by a stability testing of various blends comprising Fingolimod and excipient for 1 month at 50C. In addition to, several binders, disintegrants, lubricants, flow regulators, matrix formers, plasticizers, flavouring agents, sweeteners were marked as suitable for making solid oral formulations.

In summary, the prior art teaching indicates that SIP receptor modulators comprising an aminopropane-l,3-diol group are not easily formulateable into a stable solid oral formulation. Apparently, this is because of reactivity of the aminopropane-l,3-diol group. Only limited amount of suitable pharmaceutical excipients, particularly fillers, has been accordingly found. Thus, it will be beneficial to provide an alternate and/or improved composition for oral administration of Fingolimod, which is stable and has good handling properties in making pharmaceutical dosage forms for oral administration

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition suitable for oral administration of Fingolimod, a salt thereof or an ester thereof, which composition exhibits improved stability upon a long-term storage and has advantageous handling properties in making orally administrable final dosage forms such as capsules or tablets.

In the first aspect, the present invention relates to a pharmaceutical composition comprising Fingolimod and-or a pharmaceutically acceptable salt or ester thereof, calcium lactate pentahydrate and, optionally, a lubricant. The composition is preferably formulated in a form of a powder for oral administration and/or a compressed tablet.

In a second aspect, the invention relates to a process for making pharmaceutical composition, comprising the steps of

a) Mixing Fingolimod and/or a pharmaceutically acceptable salt or ester thereof with calcium lactate pentahydrate;

b) Optionally, screening, milling and-or granulating the mixture obtained in the step a); and

c) Mixing the mixture from the step a) or, optionally, from the step b) with a lubricant. Preferably, the pharmaceutically acceptable salt of Fingolimod is Fingolimod hydrochloride.

Preferably, the pharmaceutically acceptable ester of Fingolimod is (S)-Fingolimod phosphate.

Preferably, the lubricant is magnesium stearate.

Preferably, the mass ratio of calcium lactate pentahydrate to Fingolimod and/or a salt or ester thereof is from 99.5:0.5 to 80:20, more preferably from 99: 1 to 90: 10.

Preferably, the composition does not comprise a binder.

Preferably, the composition consists of Fingolimod and-or a pharmaceutically acceptable salt or ester thereof, calcium lactate pentahydrate and, optionally, a lubricant.

In a third aspect, the invention relates to use of calcium lactate pentahydrate for making pharmaceutical compositions comprising Fingolimod and/or a pharmaceutically acceptable salt or ester thereof.

In a fourth aspect, the invention relates to a composition comprising Fingolimod and/or a pharmaceutically acceptable salt or ester thereof, calcium lactate pentahydrate and, optionally, a lubricant, for use in medicine, preferably in treating or preventing a disease or condition treatable by Fingolimod.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an oral pharmaceutical composition, and oral dosage forms, comprising Fingolimod. The "Fingolimod" is a generically used name for 2-amino-2-[2-(4-octylphenyl)ethyl]-propane-l,3-diol and will be so used throughout the invention, unless especially disclosed to the contrary.

Fingolimod comprises a basic amino-group and may accordingly form acid addition salts with organic or inorganic acids. In accordance with its intended use, pharmaceutically acceptable acids are preferred. Examples of pharmaceutically acceptable acids are, without limitation, a hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, formic, acetic, propionic, oxalic, malonic, maleic, fumaric, lactic, citric, malic, tartaric, methane sulfonic, benzene sulfonic, naphthalene disulfonic acid, etc. Preferred pharmaceutically acceptable salt is Fingolimod hydrochloride.

Fingolimod also comprises two hydroxyl groups and may accordingly form ester(s) with inorganic or organic acid(s). In accordance with its intended use, pharmaceutically acceptable acids are preferred. The acids listed in the preceded article may be advantageously employed, without any restriction to other suitable acid. If only one hydroxyl group is substituted, a compound with a chiral carbon is formed. Accordingly, the esters may be of (R) configuration, (S) conformation or may be racemic. Any of such possibilities is covered by the term "ester" in the present invention, unless specifically state to the contrary. Preferred pharmaceutically acceptable ester is Fingolimod-phosphate ester, preferably (S)-Fingolimod-phosphate ester.

Solid state Fingolimod, a salt and-or ester thereof may exist as a crystalline and/or an amorphous product. Crystalline products may exist in different polymorphic modifications. In addition to, they may be substantially anhydrous or may exist in a form of a hydrate and/or a solvate. Any of such modifications is included within the terms "Fingolimod", "Fingolimod salt" or "Fingolimod ester" throughout the invention.

Fingolimod, a salt thereof or an ester thereof are either commercially available or may be obtained by processes known in the art.

The essential components of compositions of the present invention are Fingolimod and/or a salt or an ester thereof, and calcium lactate pentahydrate. Calcium lactate pentahydrate is a known compound approved in particular for use in food and cosmetic industry. Its use as a pharmaceutical excipient in making oral dosage forms appears not being common. Calcium lactate pentahydrate is a stable water soluble compound and may be obtained either commercially or by processes known in the art.

It was found out by the present inventor that calcium lactate pentahydrate may form stable compositions with Fingolimod and/or salts or esters thereof. The stability of such compositions in long-term storage tests is at least comparable with that of similar

compositions with mannitol, which is considered in the prior art as the most suitable filler for formulating Fingolimod into oral pharmaceutical compositions, and is superior to many other suggested fillers. The compositions of the invention exhibit good handling properties, e.g. flowability, content uniformity etc. for making powders and-or granulates both for direct oral administration and-or for tabletting. Furthermore, calcium lactate pentahydrate efficiently masks the unpleasant taste of Fingolimod without providing a sweet taste as, e.g., mannitol and similar sugar alcohols may do. Yet furthermore, calcium lactate pentahydrate is a source of soluble calcium and lactate ions, which both may contribute to the overall benefit of the patient treated by Fingolimod.

Accordingly, the present invention provides for a solid composition for oral administration comprising Fingolimod and/or a salt or ester thereof and calcium lactate pentahydrate. In an advantageous embodiment, the mass ratio of calcium lactate pentahydrate to Fingolimod and/or a salt or ester thereof is advantageously from 99.5:0.5 to 80:20, more preferably from 99: 1 to 90: 10.

In yet an advantageous embodiment, the composition of the invention comprises calcium lactate pentahydrate as the single excipient serving as a filler. Thus, in particular, the composition does not comprise a sugar alcohol such as mannitol and/or sorbitol, a phosphate such as calcium phosphate and or a cellulose such as microcrystalline cellulose.

The composition preferably further comprises a lubricant/glidant, which improves the flow of the composition and minimizes adherence to walls of equipment. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl

palmitostearate, sodium stearyl fumarate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, talc, poloxamer or a mixture of any of the above. Preferably the lubricant is a stearate, most preferably magnesium stearate. The amount of the lubricant is typically about 25-100 weight per cent in respect to the weight of the Fingolimod in the mixture.

In an advantageous embodiment, the composition does not comprise any other excipient except calcium lactate pentahydrate and lubricant. Thus, in a specific aspect, the invention provides for a pharmaceutical composition consisting of Fingolimod and/or a pharmaceutically acceptable salt or ester thereof, calcium lactate pentahydrate and, optionally, a lubricant.

The use of other excipient is not fully excluded however. In particular, the composition may optionally comprise a binder. Suitable binders may include cellulose or a cellulose derivative, e.g. hydroxypropyl cellulose or hydroxypropylmethyl cellulose. The amount of the binder may be typically from 0.05 to 5 weight per cent in respect to the weight of the Fingolimod/calcium lactate mixture.

The composition of the present invention may be formulated to final dosage forms for oral administration. Such dosage form may comprise a dose of powder or granulate comprising the composition of the invention, which is filled in a hard-shell capsule or in a sachet. Such dosage form may also comprise the composition of the invention compressed into a tablet. The tablet is preferably a swallowable tablet. It may be optionally coated by a film coat comprising, in essence, any suitable inert coating material known in the art. The dosage form advantageously comprises a unit dose of Fingolimod, which may be from 0.1 to 2 mg of Fingolimod, preferably 0.1, 0.2, 0.25, 0.5, 1.0 or 2.0 mg of Fingolimod, calculated as the free base. In total, a single dosage form may advantageously comprise from 10 to 200 mg of the composition. Preferred dosage form is a hard-shell capsule filled with a dose of the composition of the present invention in a form of powder or granulate. The hard-shell capsule may advantageously be made from gelatin.

In another aspect, the invention relates to a process for producing a pharmaceutical composition, comprising the steps of

a) Mixing Fingolimod and/or a pharmaceutically acceptable salt or ester thereof with calcium lactate pentahydrate;

b) Optionally, screening, milling and/or granulating the mixture obtained in the step a); and

c) Mixing the mixture from the step a) or, optionally, from the step b) with a lubricant More particularly, the composition as discussed above may be produced by this process.

Sub a)

The Fingolimod and-or a pharmaceutically acceptable salt or ester thereof, typically Fingolimod hydrochloride and/ or Fingolimod phosphate ester may optionally be milled and/or pre-screened before mixing in the step a) in order to remove lumps. Advantageously, the particles of the treated product pass a screen with 400-800 micrometers mesh size.

Accordingly, calcium lactate pentahydrate may be treated by the same manner.

The mass ratio of calcium lactate pentahydrate to Fingolimod and/or a salt or ester thereof is advantageously from 99.5:0.5 to 80:20, more preferably from 99: 1 to 90: 10.

The mixing step a) may advantageously comprise dry or wet mixing of components in any suitable blender at, e.g., 100 to 400 revolutions per minute. The mixing step a) also comprises mixing per partes, i.e. when the Fingolimod component is mixed first with a low amount of the calcium lactate pentahydrate, e.g. from 5 to 50 per cent of the total charge of calcium lactate pentahydrate, in order to form a pre-mix. Subsequently the remaining amount of the calcium lactate pentahydrate is added to the pre-mix in one or more doses.

While being not the preferred variant, the step a) also may comprise the step of adding a binder solution, whenever the binder is appropriate. A list of suitable binders has been provided above. Typically, the binder is added in a solution in an appropriate liquid, e.g. in water, alcohol or a mixture of both, and the mixture is subjected to a granulation in the step b). Alternately the binder is added to the mix dry and the granulation liquid is added in the granulation step b).

In the preferred variant, indeed, no binder is used.

Sub b)

The purpose of the optional step b) is to suitably modify the physical properties of the mixture from the step a) for its formulation in medicinal forms. If appropriate, the mixture may be screened, advantageously through a screen of mesh size of about 400-800 microns, and/or optionally milled on a suitable mill. If appropriate, the mixture may be granulated in a suitable high sheer mixer-granulator and-or in a fluid bed granulator. A drying step may be included as well, e.g., within the granulation process.

Sub c)

Mixing with a suitable lubricant, preferably with a stearate and most preferably with magnesium stearate, provides a free-flowing particulate composition suitable for use in making solid-state final forms discussed above. The lubricant is preferably pre-screened, e.g. with a screen of 800-900 mesh size.

In accordance with the invention, the free-flowing composition obtained in the step c), which is typically in a form of a powder or granulate is then formulated in medicinal final dosage forms. The suitable final dosage forms have been discussed above.

In summary, there has been manifested a suitability and advantage of calcium lactate pentahydrate in making Fingolimod-comprising pharmaceutical compositions. Accordingly, the specific aspect of the present invention relates to a novel and advantageous use of this compound, namely to use of calcium lactate pentahydrate for making pharmaceutical compositions comprising Fingolimod and/or a pharmaceutically acceptable salt or ester thereof.

The pharmaceutical compositions of the present invention and/or final dosage forms comprising them are useful, for treating or preventing a disease or condition treatable by Fingolimod. The "disease or condition treatable by Fingolimod" as used therein may comprise, without limitation:

= treatment and/or prevention of organ or tissue transplant rejection, particularly in the treatment of acute or chronic alio- and xenograft rejection or in the transplantation of insulin producing cells;

= treatment and/or prevention of autoimmune disease or of inflammatory conditions, e.g. multiple sclerosis, arthritis (e.g. rheumatoid arthritis), inflammatory bowel disease, hepatitis etc.;

= treatment and/or prevention of viral myocarditis and viral diseases caused by viral myocarditis, including hepatitis and AIDS.

Thus, in a particular aspect, the present invention relates to a composition comprising Fingolimod and/or a pharmaceutically acceptable salt or ester thereof, calcium lactate pentahydrate and, optionally, a lubricant, for use in medicine, preferably in treating or preventing a disease or condition treatable by Fingolimod.

The invention will be further illustrated by the following non-limiting examples.

Examples

Example 1 Pharmaceutical capsule dosage form comprising 0.5 mg of Fingolimod Com osition:

Process:

Fingolimod HC1 is blended with 12% of Calcium lactate pentahydrate for 20 min. Then the blend is sieved through a 0.5 mm sieve. Next 44% of Ca lactate is then added to the blend and blended for 20 min. In the next step 33% of Ca lactate is added (20' mix). Finally 1 1% is added and blended for 20 min more. Then the mixture is sieved, Mg stearate is added and blended for 5 min. The final blend is filled into hard gelatin capsules number 3.

Reference example

A capsule comprising composition of Fingolimod hydrochloride with calcium lactate pentahydrate and magnesium stearate has been prepared according to Example 1

(composition A). Similar capsules comprising, instead of calcium lactate pentahydrate, the same amount of another filler were prepared accordingly:

Composition B Dextran (Emdex NON)

Composition C Trehalose

Composition D Lactose

The capsules were packed in Alu-Alu blister and subjected to accelerate stability testing at 40°C/75%RH in a thermostated chamber. The marketed product Gilenya (capsules comprising 0.56 mg of Fingolimod hydrochloride, mannitol as the filler and magnesium stearate as lubricant) was used as reference.

The contents of Fingolimod as well as of impurities were determined by FIPLC.

The results of stability study were as follows:

Time t=0 Impurities in per cent

The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.