WO2019082139A1

WO2019082139A1 - Fingolimod hydrochloride liposomal injection

Info

Publication number: WO2019082139A1
Application number: PCT/IB2018/058370
Authority: WO
Inventors: Kiran K JADHAV; Raghavendra ANEGUNDI; Sreenivasa Reddy; Shivakumar PRADEEP
Original assignee: Shilpa Medicare Limited
Priority date: 2017-10-27
Filing date: 2018-10-26
Publication date: 2019-05-02

Abstract

The present invention relates to liposomal injection for patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability, more specifically, a liposomal injection containing fingolimod or pharmaceutically acceptable salts thereof and most specifically fingolimod hydrochloride salt.

Description

FINGOLIMOD HYDROCHLORIDE LIPOSOMAL INJECTION

FIELD OF THE INVENTION

The present invention provides a liposomal injection for patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability, more specifically, a liposomal injection containing fingolimod or pharmaceutically acceptable salts thereof and most specifically fingolimod hydrochloride salt. BACKGROUND OF THE INVENTION

Fingolimod hydrochloride (FTY 720), 2-amino-2-[2-(4- octylphenyl)ethyl] - propane- 1 , 3 -diol hydrochloride

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. Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate.

Fingolimod HCI is approved as Gilenya™, which is a hard-shell capsule filled by a powder comprising 0.56 mg of micronized fingolimod hydrochloride corresponding to 0.5 mg of fingolimod per capsule, for once daily administration for the treatment of relapsing remitting multiple sclerosis. Gilenya™ has very fast dissolution profile, which provide dissolution of about 99% in 30 minutes in 500 ml media constituted by 0.1 N HCL + 0.2% SLS, at 100 rpm (as specified by Office of generic drugs or OGD) Giienya™ capsule comprises mannitol as diluent, prepared by direct blending method and capsule additionally comprises small amount of magnesium stearate as a lubricant. Fingolimod HC1 was used in a micronized form to ensure content uniformity of the active substance.

However, in addition to side effects common to immunomodulatory therapy,

FTY720 was reported to cause cardiovascular complications, macular oedema, and brain inflammation, which may be due to FTY720 interacting with more than one SIP -receptor subtypes; Martin R., Nature, 464. 360-362 (2010). Accordingly, there remains a need for the development of more effective FTY720 derivatives.

Liposomes having a diameter o dispersed phospholipids bi layer in water to form spherical ultra fine particles of only several tens of nanometers to several microns; Bangham et al; J.Mol.Biol. (1965) 13, 238-252, and Gregoriadis, FEBS Letters, Vol.36, number 3 found the first application of liposomes as drug carriers. Since liposomes have a unique role characteristic, and are more of attention. Prior art shows that the main objectives of liposomes is as drug carriers, especially in cancer treatment, the use of targeting of liposomes, the liposomes as an effective carrier of anticancer drugs have wide applications. In addition, the drug is slowly released from entrapped liposomes, in the circulation than the free drug; and the liposomal drug has a longer residence time, thus prolonging the duration of action of drugs, playing a long-lasting effect; the drug due to lipid entrapment will improve the stability of the encapsulated drugs, but also is directed to certain target organ or tissue to be treated is released, so that these target organ or tissue drug concentrations increase and improve the efficacy of the drug; at the same time, some non-organ or tissue drug concentrations are located rarely avoid the effects of drugs on these organs or tissue, thereby reducing the toxicity of the drug.

Several approaches taken in an effort to increase the circulation time of liposomes and thus ensure delivery of the liposome contents to the target tissue include the following: masking the liposomes from the reticuloendothelial system recognition using a sialic acid residue coating (U.S. Pat. No. 4,501 ,728); rigidifying the liposome membrane with sphingomyelin or neutral phospholipid with predominantly saturated acyl chains containing 5 to 20% glycolipid (U.S. Pat. No. 4,920,016); forming liposomes with a 3-80 fold higher drug to lipid ratio than traditional liposome preparations in a 3 -compartment system of the agent, bi layers, and release inhibiting buffer containing citric acid (U.S. Pat. No. 6,083,530); incorporating cholesterol in the liposome; Alberto A. Gabizon, Cancer Investigation, 19(4) 424-436 (2001) and derivatizing the phospholipid with polyethylene glycol (pegylated liposomes) (U.S. Pat. Nos. 5,013,556 and 6, 132,763).

US Patent Application No. 20150157610Λ 1 discloses the poorly water-soluble substance encapsulated liposome, which is sterol-free and wherein the poorly-water soluble substance is selected from FK506, FTY720 (fingolimod) or cyclosporine A.

YiCheng et al, Nanomedicine.2014 February; 10(2):393-400 (A novel liposomal formulation of FTY720 (Fingolimod) for promising enhanced targeted delivery) discloses the free FTY720, LP-FTY720 showed improved aqueous stability and prolonged circulation time in mice.

Jitendriya Swain et al, Phys Chem Chem Phys. 2013 Nov 7: 15(41 ): 17962-70 (Study of aqueous phase aggregation of FTY720 (fingolimod hydrochloride) and its effect on DM PC liposomes using fluorescent molecular probes) discloses the aqueous phase aggregation of fingolimod hydrochloride and its effect on dirnyristoylphosphatidylcholine (DMPC) liposomes.

However, there exists a need to develop the liposomal injection for patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability, more specifically, a liposomal injection containing fingolimod hydrochloride.

SUMMARY OF THE INVENTION

In one embodiment of the invention, the present invention provides herein liposomal injection compositions consisting essentially of a therapeutically effective amount of fingolimod or pharmaceutically acceptable salts thereof and an excipient that facilitates intravenous and subcutaneous administration, and methods of use thereof for treating patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

In another embodiment, the present invention further provides the fingolimod or pharmaceutically acceptable salts thereof liposomal injection comprising fingolimod or pharmaceutically acceptable salts thereof, phospholipids, sterols, medium chain triglycerides, hydrating agent, solvent and a buffer solution.

In a further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% to about 0.15 wt% fingolimod or pharmaceutically acceptable salts thereof; about 0.4 wt% to about 1.4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0. 1 wt% to about 1 wt% 1, 2- Distearoyl-sn-glycero-3-phosphoglyceroi sodium; about 0.1 wt% to about 0.35 w†% cholesterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% to about 0.15 wt% fingolimod hydrochloride; about 0.4 wt% to about 1 .4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% 1 , 2-Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 w†% cholesterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides and pharmaceutically acceptable excipients.

In a still further embodiment the present invention provides a liposomal composition comprising of about 0.025 vvt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl- sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients. In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-DistearoyJ-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod or pharmaceutically acceptable salts thereof; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% o cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 . 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition comprising of about 0.15 wt% fingolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.3 wt% of cholesterol; about 0.3 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.15 w†% fingolimod hydrochloride; about 1.2 w†% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2-Distearoyl-sn- glycero-3 -phosphoglycero 1 sodium; about 0.3 wt% of cholesterol; about 0.3 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% to about 0.15 wt% fingolimod hydrochloride; about 0.4 wt% to about 1.4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% 1, 2-Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides; and about 1.5 wt% to about 10 wt% sucrose.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% to about 0.15 wt% fingolimod hydrochloride: about 0.4 wt% to about 1.4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% 1 , 2-Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides; and about 1.5 wt% to about 10 wt% sucrose.

In further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In another embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.05 wt% fingolimod hydrochloride: about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In another embodiment the present invention provides a liposomal composition comprising of about 0. 15 wt% fingolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.15 wt% fingolimod hydrochloride; about 1 .2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% o medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% to about 0.15 wt% of fingolimod hydrochloride; about 0.4 wt% to about 1.4 wt% of hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% of 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol, sodium; about 0.1 wt% to about 0.35 wt% of cholesterol; 0.1 wt% to about 0.35 wt% of medium chain triglycerides; about 1.5 wt% to about 10 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% to about 0.15 wt% of fingolimod hydrochloride; about 0.4 wt% to about 1.4 wt% of hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% of 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol, sodium; about 0.1 wt% to about 0.35 wt% of cholesterol; 0.1 wt% to about 0.35 wt% of medium chain triglycerides; about 1 .5 wt% to about 10 wt% of sucrose; and phosphate buffer having a pi 1 in the range of about 6.5 to about 8.0.

In further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycero! sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer hav ing a pH in the range of about 6.5 to about 8.0.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pl l in the range of about 6.5 to about 8.0.

In another embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod hydrochloride; about I wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0. In another embodiment the present invention provides a liposomal composition comprising of about 0.15 wt% fingolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pi 1 in the range of about 6.5 to about 8.0.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0. 15 wt% fingolimod hydrochloride; about 1 .2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides herein, compositions consisting essentially o a therapeutically effective amount of fingolimod hydrochloride and pharmaceutically acceptable excipients that facilitates intravenous and subcutaneous administration, and methods of use thereof for treating patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

In describing and claiming the present invention, the following terminologies will be used in accordance with the definitions set out below.

The term "multiple sclerosis (MS)" as used herein refers to as a frequent and disabling neurological disease characterized by multifocal destruction of central nervous system myelin.

As used herein in connection with numerical values, the terms "about" mean +/- 15% of the indicated value, including the indicated value. As used herein, the term "composition" refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Pharmaceutical compositions of the present invention generally contain liposomal fmgolimod hydrochloride as described herein and a pharmaceutically acceptable carrier, diluent, or excipient. By "pharmaceutically acceptable," it is meant that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and non-deleterious to the recipient thereof.

The term "liposomes" are vesicles composed of one or more concentric lipid bilayers which contain an entrapped aqueous volume. The bilayers are composed of two lipid monolayers having a hydrophobic "tail" region and a o hydrophilic "head" region, where the hydrophobic regions orient toward the center of the bilayer and the hydrophilic regions orient toward the inner or outer aqueous phase.

In a preferred embodiment, the pharmaceutical composition of the invention is liposomal injection.

In the most preferred embodiment, the pharmaceutical liposomal injection composition comprising fingolimod hydrochloride and pharmaceutically acceptable excipients.

Fingolimod or pharmaceutically acceptable salts are used for the preparation of the liposomal injection. More preferably fmgolimod hydrochloride salt is used for the preparation of pharmaceutical liposomal injection composition. Fingolimod or pharmaceutically acceptable salts thereof is used in the range of about 0.01 wt% to about 0.25 wt% based on the total weight of the composition. The more preferred concentration of fmgolimod hydrochloride in composition is about 0.02 wt% to about 0.2 wt% based on the total weight of the composition. The most preferred concentrations of fingolimod hydrochloride are about 0.025 wt%, about 0.05 wt% and about 0.15 wt% based on total weight of the composition. In another embodiment, the pharmaceutical liposomal injection composition comprising of fmgolimod hydrochloride, phospholipids, sterols, medium chain triglyceride, hydrating agent, and phosphate buffer solution.

In a still further embodiment, the fingolimod hydrochloride pharmaceutical liposomal injection of the present invention is characterized in that the liposomal formulation comprising of about 0.025 wt%, to about 0.15 wt% fingolimod or pharmaceutically acceptable salts thereof; about 0.2 wt% to about 2.5 wt% phospholipids; about 0. 1 wt% to about 0.35 wt% of sterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides, about 1.5 wt% to about 2.5 wt% hydrating agent and phosphate buffer solution having a pH range of about 6.5 to about 8.0.

Examples of the phospholipids are selected form the group consisting of a natural phospholipid, a synthetic phospholipid, and combinations thereof. Lecithin is one of the natural resources for phospholipid. Lecithin is a mixture found in egg yolk and soy et. al. It comprises a number of phospholipids including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidyl inositol (PI). Natural phospholipids also include, e.g. hydrogenated soy phosphatidyl choline (HSPC), sphingomyelin, and phosphatidylglycerol (PG). Synthetic phospholipids include, but are not limited to, derivatives of phosphocholine (for example, DDPC, DLPC, DM PC, DPPC, DSPC. DOPC, POPC, DEPC), derivatives of phosphoglycerol (for example, DMPG. DPPG, DSPG, POPG, DSPG-NA, DSPG-NH4), derivatives of phosphatide acid (for example, DMPA, DPPA, DSP A), derivatives of phosphoethanolamine (for example, DMPE, DPPE, DSPE DOPE), derivatives of phosphoserine (for example, DOPS), PEG derivatives of phospholipid (for example, mPEG-phospholipid, mPEG 2000-DSPE, polyglycerin-phospholipid, functionalized-phospholipid, and terminal activated-phospholipid). Preferably, phospholipids are selected from hydrogenated soy phosphatidyl choline (HSPC) and l ,2-Distearoyl-sn-glycero-3-phosphoglycerol, sodium salt (DSPG-Na)/N-Carbonylmethoxypolyethylenglycol-2000)-1, 2-distearoyl- sn-glycero-3-phosphoethanolamine (MPEG2000-DSPE). Phospholipids are preferably used in the pharmaceutical liposomal injection composition of about 0.2 wt% to about 2.5 wt% based on the total weight of the composition.

Examples of the sterol is selected from the group consisting of cholesterol, sitosterol, campesterol, desmosterol, fucosterol, 22-ketosterol, 20-hydroxysterol, stigmasterol, 22-hydroxychoIesterol, 25-hydroxycholesterol, !anosterol, 7- dehydrocholesterol, dihydrocholesterol, 19-hydroxycholesterol, 5a-cholest-7-en-3p- ol, 7-hydroxycholesterol, epicholesterol, ergosterol, and dehydroergosterol. Preferably, the sterol is selected from cholesterol. Sterol preferred used in the pharmaceutical liposomal injection composition of about 0.1 wt% to about 0.35 wt% based on the total weight of the composition.

Sources of medium chain triglycerides or MCTs include coconut oil, palm kernel oil, camphor tree drupes, and butter. MCT are also available as a supplement. Medium chain triglycerides are medium-chain fatty acid esters of glycerol. Medium- chain fatty acids are fatty acids containing from six to 12 carbon atoms. Coconut and palm kernel oils are also called lauric oils because of their high content of the 12 carbon fatty acid, lauric or dodecanoic acid. Medium-chain triglycerides used for nutritional and other commercial purposes are sometimes derived from lauric oils. In the process of producing MCTs, lauric oils are hydrolyzed to medium-chain fatty acids and glycerol. The glycerol is drawn off from the resultant mixture, and the medium-chain fatty acids are fractionally distilled. The medium- chain fatty acid fraction used commercially is sometimes mainly comprising the eight carbon caprylic or octanoic acid and the 10 carbon capric or decanoic acid. There are much smaller amounts of the six carbon caproic or hexanoic acid and the 12 carbon lauric acid in the commercial products. The caprylic- and capric-rich mixture is finally re-esterified to glycerol to produce medium-chain triglycerides that are mainly glycerol esters of caproic, capiylic (Cg), capric (Cio) and lauric acid in a ratio of approximately 2:55:42: 1. The Medium chain triglycerides as used in the present invention has the molecular weight of about 490 to about 495 g/mol. Medium chain triglyceride preferred used in the pharmaceutical liposomal injection composition of about 0.1 wt% to about 0.35 wt% based on the total weight of the composition.

In embodiments of the present invention provides a liposomal composition comprising of about 0.025 wt% to about 0.15 wt% fingolimod hydrochloride; about 0.4 wt% to about 1 .4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0. 1 wt% to about 1 wt% 1 , 2-Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0. 1 wt% to about 0.35 wt% medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% to about 0. 1 5 wt% fingolimod hydrochloride; about 0.4 wt% to about 1 .4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% 1 , 2-Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0. 1 wt% to about 0.35 wt% medium chain triglycerides and pharmaceutically acceptable excipients.

In a still further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl- sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In still further embodiment the present invention provides a liposomal composition consisting of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition comprising of about 0.15 wt% fingolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.3 wt% of cholesterol; about 0.3 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.15 wt% fingolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1, 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.3 wt% of cholesterol; about 0.3 wt% of medium chain triglycerides and pharmaceutically acceptable excipients.

Examples of the hydrating agent is selected from the group consisting of glucose, dextrose, sucrose, Trehalose, mannitol, lactose and any combinations thereof. Preferably, the hydrating agent is selected from sucrose. Hydrating agent preferably used in the pharmaceutical liposomal injection composition of about 1.0% to about 3% based on the total weight of the composition. Most preferably, hydrating agent is used in the composition of about 1.5% to about 10% based on total weight of the composition.

In another embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% to about 0.15 wt% fingolimod hydrochloride; about 0.4 wt% to about 1.4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% 1, 2-Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0. 1 wt% to about 0.35 wt% medium chain triglycerides; and about 1.5 wt% to about 10 wt% sucrose.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% to about 0.15 wt% fingolimod hydrochloride; about 0.4 wt% to about 1.4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0. 1 wt% to about 1 wt% 1 , 2-Distearoy!-sn-glycero-3- phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides; and about 1.5 wt% to about 10 wt% sucrose.

In another embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 t% of medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.05 wt% fmgolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- D i stearov l-sn-glyeero-3 -phosphogl cerol sodium; about 0.2 wt% of cholesterol; about 0.2 t% of medium chain triglycerides; and about 2 wt% of sucrose.

In a further embodiment the present invention provides a liposomal composition consisting of about 0.05 wt% fmgolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In another embodiment the present invention provides a liposomal composition comprising of about 0.15 wt% fmgolimod hydrochloride; about 1 .2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.15 wt% fmgolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; and about 2 wt% of sucrose.

In a still further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% to about 0.15 wt% of fmgolimod hydrochloride; about 0.4 wt% to about 1 .4 wt% of hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% of 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol, sodium; about 0.1 wt% to about 0.35 wt% of cholesterol; 0.1 wt% to about 0.35 wt% of medium chain triglycerides; about 1 .5 wt% to about 10 wt% of sucrose; and phosphate buffer having a pi I in the range of about 6.5 to about 8.0.

In another embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% to about 0.15 wt% of fmgolimod hydrochloride; about 0.4 wt% to about 1.4 wt% of hydrogenatcd soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% of 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol, sodium; about 0.1 wt% to about 0.35 wt% of cholesterol; 0. 1 wt% to about 0.35 wt% of medium chain triglycerides; about 1.5 wt% to about 10 wt% of sucrose; and phosphate buffer having a pi I in the range of about 6.5 to about 8.0.

In further embodiment the present invention provides a liposomal composition comprising of about 0.025 wt% fmgolimod hydrochloride; about 0.85 wt% hydrogenatcd soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.025 wt% fmgolimod hydrochloride; about 0.85 wt% hydrogenatcd soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

In another embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fmgolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0. In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pi 1 in the range of about 6.5 to about 8.0.

In another embodiment the present invention provides a liposomal composition consisting of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

In another embodiment the present invention provides a liposomal composition comprising of about 0.15 wt% fingolimod hydrochloride; about 1.2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2 - L) i stearoy I -sn -g 1 y c ero-3 - phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

In a still further embodiment the present invention provides a liposomal composition consisting essentially of about 0.15 wt% fingolimod hydrochloride; about 1 .2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1 , 2- Distearoyl-sn-glycero-3 -phosphoglycerol sodium; about 0.3 wt% of cholesterol; 0.3 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0.

Fingolimod HC1 encapsulated liposomes can be produced, according to a known method for producing liposomes, by adding an fingolimod HC1 solution to a solution of a lipid for forming a lipid bilayer membrane. Examples of the solvent include methanol, ethanol, isopropanol, tert-butanol, Ν,Ν-dimethylformamide and chloroform. Preferred are methanol, ethanol and chloroform.

The inventive formulation also provides for a stable fingolimod liposomal formulation such that after about 6 hours, no more than about 20%, preferably about 2% to about 18% of fingolimod hydrochloride content is released, after about 24 hours, about 35% to about 70%, of fingolimod hydrochloride content is released, after about 72 hours, about 80%, more preferably about 85% of fingolimod hydrochloride content is released in pH 6.8 phosphate buffer.

In a still further embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0, wherein liposomal composition exhibits a dissolution profile such that after about 6 hours no more than about 20% of fingolimod hydrochloride content is released, after about 24 hours about 35% to 70% of fingolimod hydrochloride content is released and after about 72 hours no less than 80% of the fingolimod hydrochloride content is released in pi I 6.8 phosphate buffer.

The inventive formulation also provides for a fingolimod liposomal formulation, wherein the liposomal particles have dio value of from about 50nm to about 60nm, further the liposomal particles have dso value of from about 60nm to about 150nm and the liposomal particles have dw value from about lOOnm to about 300nm.

In a still further embodiment the present invention provides a liposomal composition comprising of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1, 2-Distearoyl-sn- glycero-3-phosphoglycerol sodium; about 0.2 wt% of cholesterol; about 0.2 wt% of medium chain triglycerides; about 2 wt% of sucrose; and phosphate buffer having a pH in the range of about 6.5 to about 8.0, wherein the liposomal particles have dio value of from about 50nm to about 60nm, dso value of from about 60nm to about 150nm and value from about l OOnm to about 300nm.

In embodiments of the inventions the liposomal compositions of present invention are diluted for intravenous infusion with 0.9% sodium chloride or 5% dextrose at concentrations of 0.05mg/mL for the treatment of multiple sclerosis.

In embodiments of the invention the liposomal composition of present invention for the treatment o multiple sclerosis is administered to a subject intravenously or subcutaneously at a dose from about 0.5mg to about 5mg per week (e.g, from about 0.5mg, l mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg. 4.5mg and 5mg per week).

In embodiments of the invention the liposomal composition of present invention reduced cardiotoxicity (myocardial infarction, bradycardia) of fingolimod hydrochloride when administered intravenously to a subject for treatment of multiple sclerosis at a dose from about 0.5mg to about 5mg per week (e.g, from about 0.5mg, lmg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg and 5mg per week) when compared to the oral doses of fingolimod hydrochloride.

Formulations suitable for parenteral administration, such as, for example, by intraarticular, intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions. The injection solutions can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Injection solutions and suspensions can also be prepared from sterile powders, such as lyophilized liposomes. In the practice of the present invention, compositions can be administered, for example, by intravenous infusion, intraperitoneally, intravesically, or intrathecal ly. Parenteral administration and intravenous administration are preferred methods of administration. The formulations of liposome compositions can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., a liposome composition. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation. The composition can. if desired, also contain other compatible therapeutic agents.

The following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the examples below. The examples should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.

Examples 1 to 3:

Liposomal injection with the following compositions are prepared.

These Liposomal injections are prepared as follows:

Step I: Preparation of Lipid Solution

Collect 5% of solvent [2.5% of ethanol and 2.5% of methanol/chloroform] required for the batch in a rota evaporation flask, weighed quantity of lipids like I ISPC. DSPG-Na/ MPEG2000-DSPE, Medium Chain Triglycerides and cholesterol are dissolved in the solvent at 50°C to 60°C, after complete solubilization, weighed quantity of fingolimod hydrochloride is added and dissolved.

Step II : RotaEvaporation

The contents of step 1 are taken into the round bottom flask, and was placed on a rotary evaporator under the following conditions: Water bath temperature of 55-60°C, condenser coils are cooled by running cold water from chiller. Angle of rotating flask approx. 45°C. Rotation speed initially set on 4 for time period of 30 to 40 minutes and reduced to reduced to 2 till the evaporation of the ethanol and chloroform. Vacuum pump set initially for gauge reading of 4()()mbar, then increased to 100m bar with no bubbling. Rotation is continued until all the solvent had evaporated and a thin film of lipid was left on the glass.

Step 111 : Hydration

Required quantity of phosphate buffer [pH 6.8] is prepared and weighed quantity of sucrose is dissolved and add this solution to the film containing round bottom flask, flask is kept under stirring at 50°C - 60°C f r 2-4hours to hydrate the film.

Step IV: High Shear Mixing

Above liposomal suspension is subjected for high shear mixing at 2000-4000RPM for 10-15 minutes.

Step V: Micro fluidization

After high shear mixing liposome suspension is subjected for Micro fluidization at 10000 - 30000 psi for 3-5 cycles to reduce the particle size.

Step VI: Extrusion Liposome suspension is heated to 50°C-65°C and then passed through polycarbonate membranes of different size [0.2micron/0.1 micron/0.08micron/0.05micron] to get uniform distribution and desired particle size of liposomes.

Step VII: Sterile Filtration

Filter the liposomal suspension using 0.2micron filter. Fill the required quantity of the liposomes into the vials and sealed.

Example 4-6:

The process for preparation is same as disclosed in Example 1 -3.

The pH of solution, Zeta Potential, Assay and Particle size of liposomal formulations of Example 4, 5 and 6 are disclosed in Table 1 , Table 2 and Table 3 respectively at 2°C

- 8°C.

In-vitro release dissolution data of example- 5 is disclosed in Table-4. Dissolution of example-5 is performed in Phosphate Buffer of pH 6.8, 90 ml . at 40°C, 120 RPM in USP-II Apparatus at the time points of 1 , 3, 6, 9, 12, 24, 30, 36, 48, 54, 60, 72, 78, 84, 96, 102, 108, 120, 144 hours. Dilution study with physiological solutions with sodium chloride and dextrose of example-5 at concentration of 0.05mg/mL is disclosed in Table-6.

- 1

Table-3

Table - 4: In vitro release (Drug release in %) study of Example 5

Table-5: (Compatibility with 5% Dextrose solution)

D 10 in nm 61 61 61 62 62

1)50 in nm 93 94 96 92 92

D90 in nm 145 149 1 4 139 139

Z-average 89 91 92 89 89

PD1 0.095 0.129 0.136 0.082 0.078

Tablc-6 (Compatibility with 0.9% Sodium chloride solution)

Results

SI.

Test

o. RT 2-8 °C RT 2-8 °C

Initial

3 Hours 3 Hours 6 Hours 6 Hours

01 Description White translucent solution

02 pH 6.58 6.57 6.55 6.48 6.56

03 Entrapped drug (in %) 68.0 66.0 66.5 64.5 66.0

04 Free drug (in %) 30.0 31.0 30.0 32.5 28.5

05 Total assay (in %) 97.5 101.0 104.0 93.0 100.0

Osmolality

06 272 267 271 273

(mOsmo!/kg) 274

07 Zeta potential -9.2 mV -21.1 mV -17.0 mV -22.1 mV - 14.4 mV

Particle size distribution

D 10 in nm 56 56 58 57 58

D50 in nm 84 86 85 83 86

08

1)90 in nm 128 134 127 125 133

Z-average 81 83 82 83 87

PDI 0.096 0.123 0.077 0.146 0.18 Example 7: Cardiac Safety in oral and intravenous formulations (Example-5) of fingolimod HC1.

Cardiac safety of fingolimod hydrochloride formulation of the present invention example-5 was compared with oral 0.5mg capsules in 12- 14 weeks Sprague Dawley rats of 300 to 380 grams. Rats were treated with fingolimod 0.05mg/kg oral and intravenous formulations (example-5); heart rate and ECG ( RR. PR. QT, QRS and QTc intervals) was measured and the data is represented in Table-7 & Table 8 respectively Table- 7 (Heart rate of Oral and intravenous formulations)

There is no significant change in heart rate in oral and intravenous formulations.

Tabie-8 ECG at 0 hours with vehicle and after 24 hours of administration of oral and intravenous fingolimod hydrochloride.

There is a significant change in PR interval from Ohrs to 24hrs in oral formulation, whereas there is no significant change in PR interval from Ohrs to 24hrs in IV formulation.

RR interval, QRS interval, QT interval and QTc interval there is no significant change in oral and IV formulation from Ohrs to 24hrs.

Claims

We Claim

1 . A liposomal composition comprising of about 0.025 wt% to about 0.15 wt% fingolimod or pharmaceutically acceptable salts thereof; about 0.4 wt% to about 1 .4 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.1 wt% to about 1 wt% 1 , 2- Distearoyl-sn-glycero-3-phosphoglycerol sodium; about 0.1 wt% to about 0.35 wt% cholesterol; about 0.1 wt% to about 0.35 wt% medium chain triglycerides and pharmaceutically acceptable excipients.

2. The liposomal composition according to claim 1 , wherein the composition comprises f 0.025 wt% fingolimod hydrochloride; about 0.85 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphoglycerol sodium; about 0.2 wt% of cholesterol; and about 0.2 wt% of medium chain triglycerides.

3. The liposomal composition according to claim 1, wherein the composition comprises of about 0.05 wt% fingolimod hydrochloride; about 1 wt% hydrogenated soya phosphatidy l choline (HSPC); about 0.3 wt% 1 , 2-Distearoyl-sn-glycero-3- phosphogiycerol sodium; about 0.2 wt% of cholesterol; and about 0.2 wt% of medium chain triglycerides.

4. The liposomal composition according to claim 1, wherein the composition comprises of about 0.1 5 wt% fingolimod or pharmaceutically hydrochloride; about 1 .2 wt% hydrogenated soya phosphatidyl choline (HSPC); about 0.45 wt% 1. 2-Distcaroyl-sn- glycero-3-phosphoglycerol sodium: about 0.3 wt% of cholesterol; and about 0.3 wt% of medium chain triglycerides.

5. The liposomal composition according to claim 1 , wherein the composition further comprises sucrose and phosphate buffer.

6. The liposomal composition according to claim 5, wherein the composition comprises of about 2.0 wt% sucrose.

7. The liposomal composition according to claim 5, wherein the composition comprises phosphate buffer having a pH in the range of about 6.5 to about 8.0.

8. The liposomal composition according to claim 1 , wherein the composition exhibits a dissolution profile such that after about 6 hours no more than about 20% of fingolimod hydrochloride content is released, after about 24 hours about 35% to 70% of fingolimod hydrochloride content is released and after about 72 hours no less than 80% of the fingolimod hydrochloride content is released in pH 6.8 phosphate buffer.

9. The liposomal composition according to claim 1 , wherein the liposomal particles have dio value of from about 50nm to about 60nm, d₅o value of from about 60nm to about 150nm and d90 value from about l OOnm to about 300nm.

10. The liposomal composition according to claim 1 , wherein the composition is administered intravenously or subcutaneously to a subject for treatment of multiple sclerosis at a dose from about 0.5mg to about 5mg per week.