US 2004OO37875A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0037875A1 MetSelaar et al. (43) Pub. Date: Feb. 26, 2004 (54) COMPOSITION FOR TREATMENT OF (30) Foreign Application Priority Data NFLAMMATORY DISORDERS Jun. 13, 2002 (WO)........................... WO O2/45688 A2 Jul. 12, 2000 (EP)........................................ OO2O4372.7 (76) Inventors: Josbert Maarten Metselaar, Utrecht (NL); Marca Henriette M. Wauben, Publication Classification Utrecht (NL); Gerrit Storm, Utrecht (NL) 51)1) Int. Cl.Cl." ........................ A61K 9/127; A61K 31/5735 (52) U.S. Cl. ............................................ 424/450; 514/179 Correspondence Address: TRASK BRITT (57) ABSTRACT P.O. BOX 2550 A pharmaceutical composition for parenteral administration, SALT LAKE CITY, UT 84110 (US) comprising liposomes composed of non-charged vesicle forming lipids, including up to 20 mole percent of an (21) Appl. No.: 10/455,257 amphipathic vesicle-forming lipid derivatized with polyeth (22) Filed: Jun. 5, 2003 yleneglycol, and optionally including not more than 10 mole percent of negatively charged vesicle-forming lipids, the Related U.S. Application Data liposomes having a Selected mean particle diameter in the Size range between about 40-200 nm and containing a water (63) Continuation of application No. PCT/EP01/14633, Soluble corticosteroid for the site-specific treatment of filed on Dec. 7, 2001. inflammatory disorders, is provided. US 2004/0037875 A1 Feb. 26, 2004 COMPOSITION FOR TREATMENT OF liposomes are the Steroidal anti-inflammatory compounds, NFLAMMATORY DISORDERS Such as prednisone, methylprednisolone, paramethaZone, 11-fludrocortisol, triamcinolone, betamethasone and dexam CROSS-REFERENCE TO RELATED ethasone. The Steroids listed belong to the group of Steroids APPLICATION which are systemically administered. Example No. 12 is the only example of a glucocorticoid-containing PEG-liposome 0001. This application is a continuation of PCT Interna in this patent and relates to the preparation of beclometha tional Patent Application No. PCT/EP01/14633 filed on Sone dipropionate-containing PEG-liposomes. However, no Dec. 7, 2001, designating the United States of America, and in Vivo data were provided. On preparing dexamethasone published, in English, as PCT International Publication No. containing PEG-liposomes according to the disclosure in WO 02/45688 A2 on Jun. 13, 2002, the contents of the EP-0662820 and on intravenous administration of the same entirety of which is incorporated by this reference. in an in Vivo experimental arthritis model, the present inventors noted that the beneficial effects, as taught in TECHNICAL FIELD EP-0662820, could not be observed at all. There was no 0002 The invention relates generally to pharmaceutical difference in pharmacokinetic profile between a Suspension compositions, and more particularly to a pharmaceutical containing the glucocorticoid and the PEG-liposomes in composition for parenteral and intravenous administration, which the same glucocorticoid had been encapsulated. comprising liposomes composed of non-charged vesicle 0005 Since glucocorticoids often are the most effective forming lipids, including up to about 20 mole percent of an drugs in the treatment of inflammatory disorders, there is a amphipathic vesicle-forming lipid derivatized with polyeth need to provide liposomal compositions which after yleneglycol (PEG) and optionally including not more than parenteral administration can more efficiently deliver effec 10 mole percent of negatively charged vesicle-forming tive amounts of glucocorticoid at the inflamed region or lipids, the liposomes having a Selected mean particle diam tissue for enhanced and prolonged local activity. eter in the size range between about 40-200 nm and con taining a corticosteroid for the Site-specific treatment of BRIEF SUMMARY OF THE INVENTION inflammatory disorders. 0006 The invention provides a pharmaceutical compo BACKGROUND OF THE INVENTION Sition for parenteral administration, comprising liposomes composed of non-charged vesicle-forming lipids, including 0.003 Intravenous administration of compositions based up to 20 mole percent of an amphipathic vesicle-forming on PEG-containing liposomes for the site-specific treatment lipid derivatized with polyethyleneglycol and optionally of inflamed tissues and regions is already disclosed in including not more than 10 mole percent of negatively EP-0662820. It is well known that long-circulating small charged vesicle-forming lipids, the liposomes having a sized liposomes which contain non-charged or Slightly nega Selected mean particle diameter in the size range between tively charged vesicle-forming lipids, Such as PEG-lipo about 40-200 nm and containing a water soluble corticos Somes, after intravenous administration can circulate for teroid for the Site-specific treatment of inflammatory disor many hours in a volume not larger than the general circu derS. lation and therefore, in theory, are able to deliver relatively high portions of anti-inflammatory agents via extravasation 0007. The invention also provides a use of a pharmaceu at Sites of enhanced vascular permeability common to tical composition, comprising liposomes composed of non inflamed regions. Such liposomes are of particular interest in charged vesicle-forming lipids, including up to 20 mole the treatment of inflammatory diseases, e.g., rheumatoid percent of an amphipathic vesicle-forming lipid derivatized arthritis, which is a chronic autoimmune disorder, causing with polyethyleneglycol and optionally including not more joint inflammation and progressive cartilage destruction. than 10 mole percent of negatively charged vesicle-forming Although Several types of anti-rheumatic drugs are available lipids, the liposomes having a Selected mean particle diam for use, the treatment of Severe, persistent Synovitis and eter in the size range between about 40-200 nm and con acute exacerbations may require the use of Several intrave taining a corticosteroid, for the preparation of a medicament nous injections containing high doses of glucocorticoids. effective in the Site-specific treatment of inflamed tissueS or Although Systemic corticosteroids can Suppress the Symp regions after parenteral administration, characterized in that toms of the disease, adverse effects limit their use. In the corticosteroid is used in the medicament in a water addition to this, glucocorticoids Suffer from unfavorable Soluble form. pharmacokinetic behavior: Short plasma half-life values and a large distribution volume require high and repeated admin DETAILED DESCRIPTION OF THE istration in order to reach a therapeutically effective con INVENTION centration of the drug at the desired site of action. Intra 0008. It has now been found that by incorporating a water articular injection of Steroids into the affected joints is often Soluble form of a corticosteroid in long-circulating lipo used to increase the local efficacy of the glucocorticoids and Somes, composed of non-charged vesicle-forming lipids, diminish the systemic adverse effects, but this way of including up to 20 mole percent of amphipathic vesicle administration is less comfortable for the patients and not forming lipids derivatized with polyethylene glycol (PEG) feasible when multiple Small joints are affected. and optionally including not more than 10 mole percent of 0004. Also, a significant incidence of painless destruction negatively charged vesicle-forming lipids, the liposomes of the joint may be associated with repeated intra-articular having a Selected mean particle diameter in the size range injections of glucocorticoids. According to EP-0662820-B, between about 40-200 nm, an increased localization and preferred compounds for entrapment in PEG-containing improved retention of the corticosteroid at inflamed tissue US 2004/0037875 A1 Feb. 26, 2004 after one single intravenous injection of a pharmaceutical pivalate, fluorimetholone acetate, fluprednidene acetate, hal composition comprising the liposomes, can be reached as cinonide, halometasone, hydrocortisone acetate, medrySone, compared with one single intravenous injection of an aque methylprednisolone acetate, mometaSone furoate, parameta ous Solution containing the same corticosteroid compound. Sone acetate, prednicarbate, prednisolone acetate, pred nylidene, rimeXolone, tiXocortol pivalate and triamcinolone 0009. The long-circulation liposomes according to the hexacetonide. Topical corticosteroids, which undergo fast, present invention have a circulation half life of at least 6 efficient clearance as Soon as these drugs become available hours, the circulation half life being defined as the time at in the general circulation, are of Special interest. Examples which the Second linear phase of the logarithmic liposomal thereof are budesonide, flunisolide and fluticaSone propi clearance profile reaches 50% of its initial concentration, onate. By preparing a water Soluble form of the above which is the extrapolated plasma concentration at t=0. mentioned topical Steroids and encapsulating this into PEG liposomes in accordance with the present invention, it is now 0.010 The particle size of the liposomes is an important possible to Systemically administer Such corticosteroids in feature, which was demonstrated by the fact that adminis order to reach site-specific drug delivery, thereby avoiding tration of a water Soluble corticosteroid, Such as predniso adverse effects associated with Systemic treatment and over lone disodium