CLIAMS:CLAIMS

1. A pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof and dicalcium phosphate.

2. The composition according to claim 1, wherein the pharmaceutically acceptable salt of fingolimod is fingolimod hydrochloride.

3. The composition according to claim 1, wherein the ratio of dicalcium phosphate to fingolimod and/or a salt thereof is ranging from 99.5:0.5 to 80:20 w/w.

4. The composition according to claim 1, wherein the ratio of dicalcium phosphate to fingolimod hydrochloride is 98.83: 1.17 percentage w/w.

5. The composition according to claim 1, wherein the composition is devoid of any other excipient except dicalcium phosphate.

6. The composition according to claims 1, wherein the composition is formulated in the form of a powder or granulates filled into capsules for oral administration and/or of a compressed tablet.

7. A process for preparing pharmaceutical composition, comprising the steps of:-
a) Mixing fingolimod and/or pharmaceutical acceptable salt thereof with dicalcium phosphate.
b) Optionally, screening, milling and or granulating the mixture obtained in the step b) and
c) Obtaining the pharmaceutical composition.

8. A process for preparing pharmaceutical composition, comprising the steps of:-
a) providing a mixture of fingolimod and/or pharmaceutical acceptable salt along 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
b) mixing the contents of step a) with another 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
c) blend the contents of step b)
d) mixing the contents of step c) with remainder ½ amount of dicalcium phosphate of the total amount of dicalcium phosphate.
e) optionally, screening, milling and or granulating the mixture obtained in the step d) and
f) obtaining the pharmaceutical composition.

9. Use of dicalcium phosphate for preparing pharmaceutical compositions comprising fingolimod and/or a pharmaceutically acceptable salt thereof.
,TagSPECI:FIELD OF INVENTION

The invention relates to pharmaceutical compositions comprising fingolimod and the process for preparation thereof.

BACKGROUND OF THE INVENTION

Fingolimod (FTY 720) is a sphingosine 1-phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. 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.

Chemically fingolimod hydrochloride is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride and chemically represented as

The approved product of fingolimod hydrochloride is sold with the brand name Gilenya, by Novartis in US market. Fingolimod hydrochloride dosage form market in US 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 the US Patent No. 5,604,229.

US Patent No. 8,324,283 discloses a solid pharmaceutical composition suitable for oral administration comprising fingolimod 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. US ‘283 patent teaches that these compositions provide a convenient means of systemic administration of fingolimod, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage properties and in particular, the composition of the invention. Further US ‘283 patent discloses in particular, the compositions of the invention may have high level of uniformity in the distribution of fingolimod hydrochloride throughout the composition, as well as high stability. The composition disclosed 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 hydroxypropylcellulose or hydroxypropylmethylcellulose, milled and/or granulated.

US Publication No. 20100040678A1 provides the fast disintegrating solid compositions comprising fingolimod hydrochloride, an alkaline earth metal silicate and a disintegrating agent, 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 fingolimod, wherein the composition is coated by a coating comprising one or more polymer resins and one or more metal oxides.

US Patent No. 8,673,918 teaches that fingolimod is not easy to formulate in solid oral formulation and only limited excipients are potentially feasible. In particular reducing sugars are not considered due to danger of Maillard reaction with the amino group of fingolimod. Thus US ‘918 patent discloses the stable pharmaceutical compositions of fingolimod in free form and one or more excipients: fillers selected from the group consisting of lactose monohydrate, lactose anhydrous, maize starch, sucrose, and microcrystalline cellulose, citric acid and sodium hydrogen carbonate; one or more binders selected the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose; one or more disintegrants selected from the group consisting of maize starch, croscarmellose sodium, sodium carboxymethylstarch, and pregelatinized; one or more lubricants selected from the group consisting of hydrogenated castor oil and magnesium stearate; a flow regulator that is colloidal silicone dioxide; and one or more matrix formers selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, starch and povidone.

PCT Publication No. WO2013091704A1 covers the pharmaceutical composition comprising fingolimod or pharmaceutically acceptable salt or ester thereof, calcium lactate and optionally a lubricant. The oral solid dosage forms disclosed in this invention are tablets and capsules.

In summary, the prior art teaching indicates that fingolimod comprising an aminopropane-1,3-diol group are not easily formulateable into a stable solid oral formulation. Apparently, this is because of reactivity of the aminopropane-1, 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 INVENTION

The present invention relates to a pharmaceutical composition suitable for oral administration of fingolimod and/or pharmaceutical acceptable salt 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 pharmaceutical acceptable salt thereof and dicalcium phosphate. The composition is preferably formulated in a form of a powder for oral administration filled into capsules and/or a compressed tablet.

In a second aspect, the invention relates to a process for preparing pharmaceutical composition, comprising the steps of:-
a) Mixing fingolimod and/or pharmaceutical acceptable salt thereof with dicalcium phosphate.
b) Optionally, screening, milling and or granulating the mixture obtained in the step b) and
c) Obtaining the pharmaceutical composition.

In a particular aspect, the invention relates to a process for preparing pharmaceutical composition, comprising the steps of:-
a) Providing a mixture of fingolimod and/or pharmaceutical acceptable salt along 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
b) Mixing the contents of step a) with another 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
c) Blend the contents of step b)
d) Mixing the contents of step c) with remainder ½ amount of dicalcium phosphate of the total amount of dicalcium phosphate.
e) Optionally, screening, milling and or granulating the mixture obtained in the step d) and
f) Obtaining the pharmaceutical composition.

Preferably, the pharmaceutically acceptable salt of fingolimod is fingolimod hydrochloride.

Preferably, the ratio of dicalcium phosphate to fingolimod and/or pharmaceutical acceptable salt is from 99.5:0.5 to 80:20 w/w.

More preferably, the ratio of dicalcium phosphate to fingolimod hydrochloride is 98.83: 1.17 percentage w/w.

Preferably, the composition does not comprise a binder.

In a third aspect, the invention relates to use of dicalcium phosphate for preparing pharmaceutical compositions comprising fingolimod and/or a pharmaceutically acceptable salt thereof.

In a fourth aspect, the invention relates to a composition comprising fingolimod and/or a pharmaceutically acceptable salt thereof, and dicalcium phosphate for use in medicine, preferably in treating or preventing a disease or condition treatable by fingolimod.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical composition comprising fingolimod and/or a pharmaceutically acceptable salt thereof and dicalcium phosphate. The term “fingolimod” refers to fingolimod, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, complexes, and pro-drugs thereof. The term “fingolimod” further includes a moiety which yields the fingolimod active component. In preferred embodiments “fingolimod” is the hydrochloride salt form of fingolimod. As used herein, the term “complex” is intended to include any construct including fingolimod and a ligand to which it may be associated by any association, including by ionic bond, by covalent bond, by inclusion, or by any other methods of forming a complex desired.

In one embodiment according to the present invention, it provides the method of treating multiple sclerosis in a human patient by administering, preferably one time daily, pharmaceutical composition comprising 0.5mg of fingolimod hydrochloride or a pharmaceutically acceptable salt thereof and dicalcium phosphate.

The fingolimod hydrochloride used in the present invention may be in particulate form. The fingolimod hydrochloride may be any particle size desired. The fingolimod hydrochloride in the film may include smaller sized particles, intermediate sized particles, larger sized particles, and combinations thereof. For smaller sized particles, the fingolimod hydrochloride may have a particle size of about 0.5 to about 10.0 microns in diameter.

For intermediate sized particles, the fingolimod hydrochloride may have a particle size of about 1.0 to about 50.0 microns in diameter.

For larger sized particles, the fingolimod hydrochloride may have a particle size of about 3.0 to about 200.0 microns in diameter.

It was found out by the present inventor that dicalcium phosphate may form stable compositions with fingolimod and/or salts 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. Yet furthermore, dicalcium phosphate is a source of soluble calcium ions, which 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 thereof and dicalcium phosphate.

In an advantageous embodiment, the ratio of dicalcium phosphate to fingolimod and/or a salt thereof is ranging from 99.5:0.5 to 80:20 w/w.

In a further advantageous embodiment, the ratio of dicalcium phosphate to fingolimod hydrochloride is 98.83: 1.17 percentage w/w.

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 a second aspect, the invention relates to a process for preparing pharmaceutical composition, comprising the steps of:-
a) Mixing fingolimod and/or pharmaceutical acceptable salt thereof with dicalcium phosphate.
b) Optionally, screening, milling and or granulating the mixture obtained in the step b) and
c) Obtaining the pharmaceutical composition.

In a particular aspect, the invention relates to a process for preparing pharmaceutical composition, comprising the steps of:-
a) Providing a mixture of fingolimod and/or pharmaceutical acceptable salt along 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
b) Mixing the contents of step a) with another 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
c) Blend the contents of step b)
d) Mixing the contents of step c) with remainder ½ amount of dicalcium phosphate of the total amount of dicalcium phosphate.
e) Optionally, screening, milling and or granulating the mixture obtained in the step d) and
f) Obtaining the pharmaceutical composition.

In a fourth aspect, the invention relates to a composition comprising fingolimod and/or a pharmaceutically acceptable salt thereof, and dicalcium phosphate 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.

Example- 1

Pharmaceutical capsule dosage form comprising 0.5mg of fingolimod composition

Ingredient Per Capsule Percentage w/w
Fingolimod Hydrochloride 0.56mg 1.17%
Dicalcium phosphate 47.44mg 98.83%
Total Weight 48mg 100%

Process for preparation:-

Fingolimod HC1 is blended with 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate for 20 min. Then the blend is sieved through mesh #60. Next 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate is then added to the blend and blended for 20 min. Then the blend is sieved through mesh #60. In the next step the remainder ½ amount of dicalcium phosphate of the total amount of dicalcium phosphate is then added to the blend and blended for 20 minutes. Then the blend is sieved through mesh #40 to form the final blend and blended blend for 20 minutes. The final blend is filled into hard gelatin capsules size number 3.

CLAIMS

1. A pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof and dicalcium phosphate.

2. The composition according to claim 1, wherein the pharmaceutically acceptable salt of fingolimod is fingolimod hydrochloride.

3. The composition according to claim 1, wherein the ratio of dicalcium phosphate to fingolimod and/or a salt thereof is ranging from 99.5:0.5 to 80:20 w/w.

4. The composition according to claim 1, wherein the ratio of dicalcium phosphate to fingolimod hydrochloride is 98.83: 1.17 percentage w/w.

5. The composition according to claim 1, wherein the composition is devoid of any other excipient except dicalcium phosphate.

6. The composition according to claims 1, wherein the composition is formulated in the form of a powder or granulates filled into capsules for oral administration and/or of a compressed tablet.

7. A process for preparing pharmaceutical composition, comprising the steps of:-
a) Mixing fingolimod and/or pharmaceutical acceptable salt thereof with dicalcium phosphate.
b) Optionally, screening, milling and or granulating the mixture obtained in the step b) and
c) Obtaining the pharmaceutical composition.

8. A process for preparing pharmaceutical composition, comprising the steps of:-
a) providing a mixture of fingolimod and/or pharmaceutical acceptable salt along 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
b) mixing the contents of step a) with another 1/4th amount of dicalcium phosphate of the total amount of dicalcium phosphate.
c) blend the contents of step b)
d) mixing the contents of step c) with remainder ½ amount of dicalcium phosphate of the total amount of dicalcium phosphate.
e) optionally, screening, milling and or granulating the mixture obtained in the step d) and
f) obtaining the pharmaceutical composition.

9. Use of dicalcium phosphate for preparing pharmaceutical compositions comprising fingolimod and/or a pharmaceutically acceptable salt thereof.

Dated this 17th day of July 2015

Dr.Akshay Kant Chaturvedi
Head-Corporate IPM & Legal Affairs
Shilpa Medicare Ltd

ABSTRACT

The present invention relates to a pharmaceutical composition comprising fingolimod and/or pharmaceutical acceptable salt thereof and dicalcium phosphate. The composition is preferably formulated in a form of a powder for oral administration filled into capsules and/or a compressed tablet.