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US 20140065203A1 (19) United States (12) Patent Application Publication (10) Pub. N6.: US 2014/0065203 A1 PeresWetoff-Morath et al. (43) Pub. Date: Mar. 6, 2014

(54) - AND (60) Provisional application No. 60/712,822, ?led on Sep. CORTICOSTEROID-CONTAINING 1, 2005. LIPOSOME COMPOSITION AND ITS USE FOR THE MANUFACTURE OF A Publication Classi?cation MEDICAMENT FOR TREATING RHINITIS AND RELATED DISORDERS (51) Int. Cl. A61K 31/58 (2006.01) (71) Applicant: BiolipoX AB, Solna (SE) A61K 31/56 (2006.01) A61K 31/4545 (2006.01) (72) Inventors: Lena PeresWetoff-Morath, Solna (SE); A61K 31/4965 (2006.01) Anders Carlsson, Stockholm (SE); (52) U.s. c1. Torbjom Bjerke, Solna (SE) CPC ...... A61K 31/58 (2013.01); A61K 31/4965 (2013.01); A61K31/56 (2013.01); A61K (73) Assignee: BiolipoX AB, Solna (SE) 31/4545 (2013.01) (21) App1.No.: 13/954,694 USPC ...... 424/450; 514/171 (22) Filed: Jul. 30, 2013 (57) ABSTRACT Related US. Application Data There is provided homogeneous pharmaceutical composi tions for the treatment of, for example, rhinitis, asthma and/or (63) Continuation of application No. 11/991,091, ?led on chronic obstructive pulmonary disease comprising a corticos Apr. 10, 2009, ?led as application No. PCT/GB2006/ teroid and an antihistamine, a polar lipid liposome and a 003222 on Aug. 31, 2006. pharmaceutical-acceptable aqueous carrier. US 2014/0065203 A1 Mar. 6, 2014

ANTIHISTAMINE- AND onset of action and feWer side effects. At present, hoWever, CORTICOSTEROID-CONTAINING dihydrochloride is not an approved medicine for LIPOSOME COMPOSITION AND ITS USE local administration, although it has been administered in that FOR THE MANUFACTURE OF A manner in clinical trials. MEDICAMENT FOR TREATING RHINITIS [0010] In one trial (Francillon C, Pécoud A. E?‘ect of nasal AND RELATED DISORDERS spray ofcetirizine in a nasal provocation test with allergen. J. Allergy Clin. Immunol. 1993:91, Suppl. 2:258 (abstract)), FIELD OF THE INVENTION cetiriZine nasal spray Was found to reduce symptoms and [0001] This invention relates to compositions for use in increase nasal peak ?oW after an allergen challenge. Further, methods of treating certain in?ammatory disorders, such as in exercise-induced asthma, a good protective effect Was seen rhinitis, asthma and chronic obstructive pulmonary disease When cetiriZine mist Was administered to the lung With a (COPD), and to processes for the preparation of such com nebuliZer (Ghosh S K, De Vos C, Mcllroy l, Patel K R. E?‘ect positions. ofcetirizine on exercise induced asthma, Thorax 1991 April; 46(4), 242-4). BACKGROUND AND PRIOR ART [0011] Some effect Was seen on symptoms When cetiriZine (presumably as the di-hydrochloride) Was given as a nasal [0002] There are many diseases/disorders that are in?am spray in patients With perennial allergic rhinitis. Concentra matory in their nature. In?ammatory diseases that affect the tions of 0.625, 1.25, and 2.5 mg/mL of cetiriZine Were population include asthma, rhinitis, COPD, in?ammatory sprayed three times a day for tWo Weeks (Clement P, Roovers boWel disease, rheumatoid arthritis, osteoarthritis, conjunc M H, Francillon C, Dodion P. Dose-ranging, placebo-con tivitis and dermatitis. trolled study ofcetirizine nasal spray in adults with perennial [0003] Asthma is a disease of the airWays that contains allergic rhinitis, Allergy 1994 September; 49(8), 668-72). elements of both in?ammation and bronchoconstriction. The most common side effects Were related to nasal events, Treatment regimens for asthma are based on the severity of although no difference in incidence betWeen the placebo and the condition. Mild cases are either untreated or are only the cetiriZine-treated groups Was seen. HoWever, the authors treated With inhaled [3-agonists Which affect the bronchocon of this article speculated therein that local irritation had an striction element, Whereas patients With more severe asthma adverse effect on treatment e?icacy. are typically treated regularly With inhaled corticosteroids [0012] Indeed, due to the irritation of the nasal mucosa by Which to a large extent are antiin?ammatory in their nature. cetiriZine, it has been found to be necessary to decrease its [0004] Allergic and non-allergic rhinitis are common dis immediate exposure in nasal administration. In European orders affecting about 30% of the population. Rhinitis has a Patent No. EP 605 203 B 1, it has been reported that this can be considerable impact on quality of life. In fact, rhinitis is achieved by providing cetiriZine in form of a composition generally considered to affect the quality of life more so than, containing cyclodextrin. e.g., asthma. [0013] Liposomes (also knoWn as lipid vesicles) are colloi [0005] Hay fever and perennial allergic rhinitis are charac dal particles that are prepared from polar lipid molecules terised by sneeZing, rhinorrhea, nasal congestion, pruritus, derived either from natural sources or chemical synthesis. conjunctivitis and pharyngitis. ln perennial rhinitis, chronic Such spherical, closed structures composed of curved lipid nasal obstruction is often prominent and may extend to eus bilayers, are typically used to entrap drugs, Which are often tachian tube obstruction. cytotoxic, in order to reduce toxicity and/ or increase ef?cacy. [0006] Oral or local are ?rst line treatments, Liposome-entrapped drug preparations are often provided in and nasal steroids second line treatments for rhinitis. For most a dry (e.g. freeZe-dried) form, Which is subsequently recon patients, topical corticosteroids and long acting antihistamine stituted With an aqueous solution immediately prior to admin agents provide signi?cant relief of symptoms.Antihistamines istration. This is done in order to minimise the possibility of may also affect non-immunologically (non-lgE) mediated leakage of eg cytotoxic drug into aqueous solution and hypersensitivity reactions such as non-allergic rhinitis, exer thereby reducing the entrapping effect of the liposome. cise induced asthma, cold urticaria, and non-speci?c bron [0014] Liposomes have also been employed to encapsulate chial hyperreactivity. various drug compounds for delivery via the nasal route, in [0007] CetiriZine, [2-{4-[(4-chlorophenyl)phenylmethyl] order to improve bioavailability or as an adjuvant. Drugs that 1-piperaZinyl}ethoxy]acetic acid, is an orally and locally may be mentioned include tetanus toxoid vaccine, insulin, active, potent, long acting peripheral H1 receptor desmopressin and hydrochloride (see antagonist. CetiriZine (in the form of the dihydrochloride salt) Turker et al, Review Article: Nasal Route and Drug Delivery is one of the most Widely used second generation antihista Systems, Pharm. World Sci., 2004; 26, 137-142 and the ref mines for the treatment of rhino-conjunctivitis and urticaria. erences cited therein), as Well as cipro?oxacin, CM3 and It is effective, Well tolerated and safe When used orally in a salbutamol (see Desai et al, A Facile Method of Delivery of dose of 10 mg daily. Sedation and dry mouth do hoWever Liposomes by Nebulization, J. Control. Release, 2002; 84, occur as side effects in orally treated patients. CetiriZine is 69-78). also approved in children for the treatment of rhinitis. [0015] Examples of formulations comprising inter alia [0008] The main clinical effects of antihistamines include liposome-encapsulated active ingredients are discussed in reduced sneeZing and rhinorrhea. HoWever, nasal blockage US. Pat. No. 4,427,649, US. Pat. No. 4,839,175, US. Pat. appears to be less responsive. Local administration of anti No. 5,569,464, EP 249 561, WO 00/38681, WO 88/01862, (such as and ) has advan WO 98/58629, WO 98/00111, WO 03/105805, US. Pat. No. tages, including rapid onset of action and feWer side effects. 5,049,388, US. Pat. No. 5,141,674, US. Pat. No. 5,498,420, [0009] Local administration of antihistamines (such as US. Pat. No. 5,422,120, WO 87/01586, WO 2005/039533, aZelastine and levocabastine) has advantages, including rapid US 2005/0112199 and US. Pat. No. 6,228,393. US 2014/0065203 A1 Mar. 6, 2014

[0016] Combination therapies comprising co-administra is intended to encompass formulations that include only com tion of antihistamines and corticosteroids are described in ponents that are regarded in the art as suitable for admini stra WO 97/01337, WO 97/46243, WO 98/48839 and WO tion to mammalian, and especially human, patients. In the 03/049770. context of the present invention, the teen may also mean that [0017] Liposome-entrapped cetiriZine has been adminis the compositions of the invention are in a form of a liquid that tered topically to evaluate peripheral antihistaminic activity is ready-to-use, directly from the shelf, and not a formulation and systemic absorption in a rabbit model (ElZainy et al, in Which drugs are encapsulated inside liposomes requiring Cetirizine from Topical -Hydrogenated reconstitution shortly prior to administration in order to avoid Liposomes, The AAPS Journal, 2004; 6, 1-7, see also Drug leakage of drugs from liposomes into an aqueous carrier. Development and Industrial Pharmacy, 2005; 31, 281-291). [0025] By “homogeneous” We include not only that the [0018] The lipophilic behaviour of the cationic (Wherein compositions of the invention comprise liposomes dispersed the anion is chloride), ZWitterionic, and anionic forms of evenly throughout the aqueous carrier, but further that active cetiriZine in buffered aqueous phosphatidylcholine liposome ingredients are distributed throughout the Whole composi systems containing from about 1 to 33.5 mg/mL of phospho tion. This means that no process steps are performed that may lipid has also been studied (Plemper van Balen G et al., serve to increase entrapment, or encapsulation, ef?ciency of Lipophilicity behaviour of the zwitterionic antihistamine active ingredient(s) into liposomes, such as remote loading cetirizine in phosphatidylcholine liposomes/water systems, (an ‘active’ loading method in Which preformed liposomes Pharm. Res. 2001; 18, 694-701). The aim With the study, in and active ingredient(s) are incubated under a transmembrane Which separate solutions of PBS-diluted egg, phosphatidyl gradient, e.g. pH, resulting in high encapsulation ef?ciency), liposomes Were poured into separate compartments and/or that, folloWing formation of a mixture comprising of dialysis cells, Was to gain insight into the mechanism of liposomes and active ingredients in aqueous medium, active interaction of the various electrical species of cetiriZine and ingredients that are not encapsulated Within liposomes are not other drugs With liposomal membranes. The ZWitterionic removed folloWing liposome formation. This may, in the case form of cetiriZine, Which dominates in the pH range of from of certain compositions of the invention, result in a substan about pH 4 to about pH 7, and even from about pH 3 to about tially similar concentration of one or more of the active ingre pH 8, Was considered by the authors of this article to be dients in the relevant aqueous medium, Whether that medium prevented from entry into the liposomal membrane by ren is located inside or outside of the liposomal structures. By dering the formation of lipophilic folded conformers of ceti “substantially similar”, We include that the concentration riZine more dif?cult. In this respect, cetiriZine Was not may vary by about 150%, such as about 140%, preferably entrapped in liposomal membranes for delivery of drug to about 130%, more preferably about 120% and particularly patients. about 110% (When comparing concentrations inside and out [0019] Homogeneous pharmaceutical compositions con side of the liposomal structures) at room temperature and taining cetiriZine and a polar lipid liposome have been dis atmospheric pressure. Drug concentration pro?les may be closed in international patent application WO 2005/ 10771 1. measured by standard techniques knoWn to the skilledperson, [0020] HoWever, none of the above-mentioned references such as 31P-NMR. For example, a standard in situ probing disclose or suggest any liposomal pharmaceutical composi technique, or a technique that involves separation of the lipo tion comprising a combination of corticosteroid and antihis somal fraction from the free aqueous carrier and measure tamine. ment of the amount/concentration of active ingredient(s) [0021] Surprisingly, We have found that the irritation that associated With each fraction may be employed. Separation may be associated with (eg nasal) administration of certain may be accomplished by centrifugation, dialysis, ultra?ltra antihistaminic active ingredients, including cetiriZine, may tion, or gel ?ltration. be reduced by Way of use of homogeneous pharmaceutical [0026] It is preferred that the compositions of the invention compositions comprising such an active ingredient, a polar further include a pharmaceutically-acceptable buffer capable lipid liposome and a pharmaceutically acceptable carrier. of providing a pH of from about pH 4 to about pH 8, prefer [0022] According to the present invention, there is provided ably from about pH 5 to about pH 7. Appropriate buffers a homogeneous pharmaceutical composition suitable for the include those that Will not interfere With the formation of treatment of, for example, rhinitis comprising, as active ingre liposomes, such as a phosphate (e.g. disodium phosphate, dients, an antihistamine and a corticosteroid, as Well as polar dipotassium phosphate, sodium dihydrogen phosphate, lipid liposomes and a pharmaceutically-acceptable aqueous potassium dihydrogen phosphate or phosphoric acid plus carrier, Which compositions are referred to hereinafter as “the base), citrate (eg sodium citrate or citric acid plus base), or compositions of the invention”. acetate (eg sodium acetate or acetic acid plus base) buffer, [0023] The skilled person Will appreciate that the relevant Which is capable of maintaining a pH Within the above-speci active ingredients are employed in compositions of the inven ?ed ranges. Buffers may be employed in an amount that is tion in pharmacologically-effective amounts (vide infra). The suitable to provide for the above-mentioned effects and such term "pharmacologically-effective amount” refers to an Will be appreciated by the skilled person Without recourse to amount of relevant active ingredient, Which is capable of inventive input. Appropriate quantities are for example in the conferring the desired therapeutic effect on a treated patient, range of about 1 mg/mL to about 30 mg/mL. Whether administered alone or in combination With the other, [0027] Compositions of the invention ?nd particular utility or another, active ingredient. Such an effect may be objective in the treatment of allergic disorders, such as asthma and (i.e. measurable by some test or marker) or subjective (i.e. the rhinitis, as Well as COPD. subject gives an indication of, or feels, an effect). [0028] Compositions of the invention ?nd particular utility [0024] By “pharmaceutical compositions” We include in the treatment of rhinitis. The term “rhinitis” Will be under compositions that are suitable for use in direct administration stood to include any irritation and/or in?ammation of the to mammals, and especially humans. In this respect, the term nose, Whether allergic or non-allergic, including seasonal US 2014/0065203 A1 Mar. 6, 2014

rhinitis (e.g. caused by outdoor agents such as pollen; hay ate salts, etc and/or as described in “Handbook ofPharma fever) and/or perennial rhinitis (e.g. caused by house dust ceulical Salts”, Eds. Stahl and Wermuth, Wiley, 2002, mites, indoor mould etc), as Well as the symptoms thereof. Chapter 12. [0029] Corticosteroids that may be mentioned include [0035] When the antihistamine active ingredient that is alclometasone, beclometasone, betamethasone, budesonide, employed is cetiriZine, preferred salts include chloride salts, ciclesonide, clobetasol, clobetasone, de?aZacort, deprodone, hydrochloride (e. g. dihydrochloride) salts and nitrate (e.g. dexamethasone, di?ucortolone, ?uocinolone, etiprednol, dinitrate) salts of cetiriZine. More preferred salts include ceti ?unisolide, ?uocinonide, ?uocortolone, ?uprednidene, ?uo riZine dinitrate and, especially, cetiriZine dihydrochloride. rometholone, ?uticasone, halcinonide, hydrocortisone, KSR [0036] The absolute and relative amounts of active ingre 592, loteprednol, methylprednisolone, mometasone, pred dients that may be employed in preparation of compositions nisolone, rimexolone and triamcinolone and commonly of the invention may be determined by the physician, or the employed salts thereof. skilled person, in relation to What Will be most suitable for an [0030] More preferred corticosteroids include budesonide, individual patient. This is likely to vary With the nature of the ciclesonide, ?uticasone, triamcinolone and mometasone and active ingredients that are employed, the severity of the con commonly employed salts thereof, and particularly budes dition that is to be treated, as Well as the species, age, Weight, onide and ?uticasone (eg the latter in the form of a salt, such sex, renal function, hepatic function and response of the par as a propionate salt). ticular patient to be treated. It is preferred hoWever that the [0031] Antihistamines may comprise H1 receptor antago compositions of the invention comprise active ingredients (or nists. Hl antagonists that may be men salts), in a total amount of from about 0.1 mg/mL to about 200 tioned include , , anataZoline, astemi mg/mL calculated on the free-base forms. Zole, , aZelastine, , , [0037] The total amounts of the active ingredients that are , bromopheniramine, , , present may be su?icient to provide a daily dose per unit cetiriZine, chlorocycliZine, , chlorophe dosage that is appropriate for the respective active ingredients namine, , , , , that are employed. For example, this may be in the range , , , , dex about 20 pg to about 200 mg. chlorpheniramine, , , dimeto [0038] Individual concentrations and dosing regimens for tiaZine, diphenhydramine, piphenylpyraline, , antihistamines are in the ranges of about 0.5 (such as about , e?etiriZine, , , , 0.7, eg about 1 mg/mL) to about 150 mg/mL, and about 0.2 , ?unariZine, homochlorocycliZine, hydrox mg to about 200 mg, respectively. Individual concentrations yZine, , levocarbastine, , lorata and dosing regimens for corticosteroids are in the ranges of dine, mebhydroline, mecloZine, , , about 50 pg to about 1,500 ug/mL, and about 20 (eg about , , niapraZine, , oxato 50) pg to about 1,600 pg, respectively. mide, , , , phe niramine, , , pipinhydrinate, [0039] The skilled person Will appreciate that compositions , , , , setas of the invention may be dosed once or more times daily in one tine, , , , thonZy or more administrations in order to provide the aforemen lamine, , trimethobenZamine, , tioned daily dose(s). and and commonly employed salts [0040] When the antihistamine active ingredient that is thereof. employed is cetiriZine, compositions of the invention com [0032] More preferred antihistamines include prise cetiriZine or a salt thereof in an amount of from about 1 and, more particularly, aZelastine, fexofenadine, more pref mg/mL to about 30 (eg about 25, such as about 23) mg/mL erably levocetiriZine and, most preferably, cetiriZine and calculated on the ZWitterionic form, preferably in an amount commonly employed salts thereof. of from about 5.5 mg/mL to about 22 mg/mL. A further preferred range is betWeen about 6 mg/mL and about 15 [0033] Unless above-mentioned active ingredients are already provided in diasteromerically (or enantiomerically) mg/mL, such as about 8 mg/mL to about 12 mg/mL. In such enriched form, individual diastereoisomers and enantiomers a case, the total amount of cetiriZine that may be present may be su?icient to provide a daily dose of cetiriZine per unit of active ingredients, and mixtures of such diastereoisomers/ enantiomers may be used in compositions of the invention. dosage that is in the range about 4 mg to about 20 mg, such as about 5 mg to about 15 mg, more preferably about 7 mg to [0034] Furthermore, any pharmaceutically-acceptable salt about 12 mg and most preferably about 8 mg to about 10 mg. of an active ingredient, as Well as the free base form thereof may be used in the manufacture of compositions of the inven [0041] The above-mentioned dosages of active ingredients tion. Preferred salts include acetate salts, acetonate salts, alu are exemplary of the average case; there can, of course, be minium salts, ammonium salts, arginine salts, bromide salts, individual instances Where higher or loWer dosage ranges are butyrate salts, calcium salts, chloride salts, choline salts, cit merited, and such are Within the scope of this invention. rate salts, diethanolamine salts, diethylamine salts, dipropi [0042] The term “liposome” Will be Well understood by onate salts, embonate salts, ethanolamine salts, ethylenedi those skilled in the art to include a structure consisting of one amine salts, forrnate salts, fumarate salts, fuorate salts, or more concentric spheres of polar lipid bilayers separated hydrobromide salts, hydrochloride salts, imidaZole salts, lac by Water or aqueous buffer compartments. tate salts, lysine salts, magnesium salts, malate salts, maleate [0043] Liposomes may be prepared by various methods salts, malonate salts, meglumine salts, mesilate salts, mor using solvents, reduced pressure, tWo-phase systems, freeZe pholine salts, nitrate salts, phosphate salts, salts, drying, sonication etc. described, for instance, in Liposome potassium salts, propionate salts, sodium salts, succinate Drug Delivery Systems, Betageri GV et al., Technomic Pub salts, sulfate salts, tartrate salts, teoclate salts, para-toluene lishing AG, Basel, SWitZerland, 1993, the relevant disclosures sulfate salts, triethanolamine salts, triethylamine salts, valer in Which document are hereby incorporated by reference. US 2014/0065203 A1 Mar. 6, 2014

[0044] The term “polar lipid” Will be Well understood by may be used in order to obtain the key phospholipid interme the skilled person to include any lipid With a polar head-group diates, 1,2-diacylglycerol, from (S)-1,2-isopropylideneglyc and tWo fatty acid residues, Which is capable of forming erol, the latter providing the glycerol backbone that is char liposomes. acteristic of phospholipids. 1,2-Diacetylated phospholipids [0045] Polar lipids, such as those described hereinafter, may then be obtained When the corresponding polar head may be of a natural and/or a synthetic/semi-synthetic origin. group is attached via chemical synthesis to the 1,2-diacylg Mixtures of natural and synthetic/semi-synthetic polar lipids lycerol intermediate. Generally, hoWever, the origin of glyc may also be employed in compositions of the invention. erol and the fatty acids used in the various steps may be of [0046] Polar lipids that may be employed in compositions both natural and synthetic origin. Synthetic and/ or semi-syn of the invention may thus be based on, for example, phospho thetic phospholipids that may be mentioned include dilau lipids, and in particular phosphatidylcholine (PC), phosphati rylphosphatidylcholine (DLPC), dimyristolphosphatidyl dylglycerol (PG), phosphatidylinositol (PI), phosphatidic choline (DMPC), dipalmitoylphosphatidylcholine (DPPC), acid (PA), phosphatidylserine (PS), or mixtures thereof. dilaurylphosphatidylglycerol (DLPG), dimyristolphosphati [0047] Phospholipids that may be employed in composi dylglycerol (DMPG), dioleoylphosphatidylcholine (DOPC) tions of the invention comprise polar and non-polar groups and dioleoylphosphatidylglycerol (DOPG). DOPC and linked to a backbone entity carrying hydroxyl groups, such as DMPC are preferred, for example in combination With one or glycerol. more of the Lipoid phospholipids mentioned hereinbefore. [0048] Phospholipids may also be represented by the gen [0056] The polar lipid may alternatively comprise or, more eral formula I, preferably, consist of a glycolipid. In the context of the present invention, the term “glycolipid” designates a com pound containing one or more monosaccharide residues bound by a glycosidic linkage to a hydrophobic moiety such as an acylglycerol, a sphingoid or a ceramide (N -acylsphin goid). [0057] A glycolipid may be a glycoglycerolipid. In the context of the present invention, the term “glycoglycerolipid” designates a glycolipid containing one or more glycerol resi dues. According to a preferred aspect of the invention, the glycoglycerolipid comprises, or consists of, galactoglycero lipid, more preferably a digalactosyldiacylglycerol of the general formula II, wherein R1 and R2 independently represent a saturated or 11 unsaturated (e.g. alkenyl), branched or straight chain alkyl OH group having betWeen 7 and 23 carbon atoms, preferably between 11 and 19 carbon atoms; and R3 represents an amide OH or ester bonding group, such as 0 [0049] iCH2iCH(OH)4CH2OH (phosphatidylglyc erol), O OH [0050] iCH2iCH2iN(CH3)3 (phosphatidylcholine), O OH [0051] iCHziCHziNHz (), R1 0 OH [0052] iH (phosphatidic acid), or 0 [0053] iCH2iCH(NH2)iCOOH (phosphatidylserine). [0054] The phospholipid may be of natural origin. Natural R2\"/O 0 OH phospholipids are preferably membrane lipids derived from O OH various sources of both vegetable (e.g. rapeseed, sun?ower, etc., or, preferably, soybean) and animal origin (e.g. egg yolk, wherein R1 and R2 are as hereinbefore de?ned. bovine milk, etc.). Phospholipids from soybean, a major [0058] The glycolipid may alternatively be a glycosphin source of vegetable phospholipids, are normally obtained golipid. In the context of the present invention, the term from the by-products (i.e. ) in the re?ning of crude “glycosphingolipid” designates a lipid containing at least one soybean oil by the degumming process. The lecithins are monosaccharide residue and either a sphingoid or a ceramide. further processed and puri?ed using other physical unit The term may thus comprise neutral glycosphingolipids, such operations, such as fractionation and/or chromatography. as mono- and oligoglycosylsphingoids as Well as oligo- and, Other phospholipids may be obtained, for example, by press more preferably, monoglycosylceramides. The term addi ing various suitable seeds and grains, folloWed by solvent tionally comprises acidic glycosphingolipids such as sia extraction and then further processing as described above. loglycosphingolipids, uronoglycosphingolipids, sulfogly Phospholipids of natural origin that may be mentioned cosphingolipids, phosphoglycosphingolipids, and include for example those that are available under the trade phosphonoglycosphingolipids. The glycosphingolipid can be names Lipoid S75, Lipoid S100 and Lipoid S75-3N (Lipoid ceramide, monohexosylceramide, dihexosylceramide, sphin GmbH, Germany), Which are all blends of several different gomyelin, lysosphingomyelin, sphingosine, or a mixture phospholipids that are found in soybean. thereof. Preferably the glycosphingolipid is sphingomyelin [0055] The phospholipid may alternatively be of synthetic or a product derived therefrom. The sphingomyelin content is or semi-synthetic origin (i.e. prepared by chemical synthe preferably established by chromatographic methods. Sphin sis). For example, a multi-step chemical synthetic approach gomyelin may be extracted from milk, preferably bovine US 2014/0065203 A1 Mar. 6, 2014

milk, brain, egg yolk or erythrocytes from animal blood, for liquid pharmaceutical compositions are benZalkonium preferably sheep. For the avoidance of doubt, synthetic and chloride, benZoic acid, butylated hydroxyanisole, butylpara semi-synthetic sphingolipids are comprised by the invention. ben, chlorbutanol, ethylparaben, methylparaben, propylpara [0059] The glycolipid may alternatively be a glycophos ben, phenoxyethanol or phenylethyl . Preferred pre phatidylinositol. In the context of the present invention, the servatives include benZalkonium chloride. Other term "glycophosphatidylinositol” designates a glycolipid preservatives that may be mentioned include sorbic acid. containing saccharides glycosidically linked to the inositol [0069] In order to retain the composition of the invention at moiety of phosphatidylinositols. its application site it may also comprise viscosity-increasing [0060] Preferred glycolipids include digalactosyldiacylg agent such as, for instance, hydrophilic polymers like poly lycerol (DGDG). ethyleneglycol, or crosslinked polyvinylpyrrolidone and/or [0061] It is preferred that the polar lipid is based on a cellulose derivatives such as hydroxypropylmethyl cellulose. phospholipid and, more particularly, a phospholipid derived Viscosity increasing agents may also function as protective from soybean (e.g. Lipoid 5100 or Lipoid S75-3N). colloids to physically stabilise the composition of the inven [0062] Preferred polar lipids (such as phospholipids) are tion prior to administration. Preferred protective colloids those that sWell to a measurable degree in Water and/or those include hydroxypropylmethyl cellulose and, more particu Which are capable of spontaneous liposome formation. larly, polyethylene glycol. [0063] If the polar (e.g. phospho-) lipid does not sWell [0070] Compositions of the invention may also comprise spontaneously in Water, the skilled person Will appreciate that ?avourings (e.g. lemon, menthol or peppermint poWder) and/ it is nevertheless possible to obtain liposomes by adding a or sWeeteners (e.g. neohesperidin). more polar, sWellable (e.g. phospho-) lipid, such as an anionic [0071] Compositions of the invention may also comprise (e.g. phospho-) lipid (e.g. phosphatidylglycerol). tonicity-modifying agents, such as sodium chloride, potas [0064] Liposome formation may be performed at above sium chloride, glycerol, glucose, dextrose, sucrose, mannitol, about 0° C. (e.g. room temperature) if the phase transition etc. temperature of the acyl chains (chain melting; gel-to-liquid [0072] Optional additives, including buffering agents, pre crystals) is beloW the freeZing point of Water. servatives, viscosity-increasing agents, antioxidants, tonic [0065] Whichever polar lipid substance (or combination ity-modifying agents and chelating agents should be selected, thereof) is used, suitable total amounts/concentrations of lip in terms of their identity and the amounts employed, keeping id(s) that may be employed in preparation of a composition of in mind that their detrimental effect on liposome stability the invention are in the range of about 10 mg/mL to about 120 should be kept at a minimum. For a given agent this can be mg/mL. Compositions of the invention that may be men ascertained by simple experiments, Which are Well Within the tioned include those in Which, When the polar lipid comprises understanding of the skilled person. Suitable amounts of such phospholipid (Whether in combination With another lipid or ingredients are hoWever in the range about 0.01 mg/mL to otherWise), the amount of phospholipid(s) in the composition about 10 mg/mL. It is preferred that the compositions of the is from about 10 (eg about 17, such as about 20) mg/mL to invention contain at least one preservative, antioxidant, about 120 mg/mL, more preferably from about 25 (e. g. about chelating agent, buffering agent and/or viscosity-increasing 35) mg to about 100 (eg about 70, such about 50, eg about agent. Suitable amounts of any/ all of these optional additives 40) mg/mL. Typical ranges that may be mentioned include include from about 0.02 to about 5 (e. g. about 3) mg/mL (eg from about 25 (eg 27) mg/ml, to about 50 mg/mL (eg 45 or, from about 0.1 to about 2 mg/mL). more particularly, 35 mg/mL). Further, the total amount of [0073] There is also provided a process for preparing com phospholipid (When the polar lipid comprises phospholipid) positions of the invention. We have surprisingly found that is preferably in the range from about 10 mg to about 80 mg liposomes may be prepared by direct sWelling of the polar (such as from about 17 (eg 20) mg to about 70 (eg 40) mg). lipids in an aqueous medium Without the addition of any other [0066] Compositions of the invention may also comprise an excipients such as charged lipids and/ or surfactants etc., antioxidant, such as ot-tocopherol, ascorbic acid, butylated Which are normally required. hydroxyanisole, butylated hydroxytoluene, citric acid, [0074] According to a further aspect of the invention, there fumaric acid, malic acid, monothioglycerol, propionic acid, is provided a process for preparing a composition of the propyl gallate, sodium ascorbate, sodium bisul?te, sodium invention, Which process comprises: metabisul?te, potassium metabisul?te, sodium sul?te, tar (a) mixing together, in an aqueous medium, a corticosteroid, taric acid or vitamin E. Preferred antioxidants include buty an antihistamine and a polar lipid, or a mixture of polar lipids, lated hydroxytoluene, ot-tocopherol, ascorbic acid and buty that is/are sWellable in aqueous media; and lated hydroxyanisole. (b) homogenising the preparation. [0067] According to the invention a chelating agent may be [0075] Step (a) of the above-mentioned process is prefer used to reduce the metal ion catalysed oxidation of phospho ably carried out in the presence of suitable agitation (e.g. lipid and/or active ingredient(s). Examples of useful chelat stirring). ing agents are ethylenediaminetetraacetic acid (EDTA) and [0076] The aqueous medium may comprise Water, saline or salts thereof (eg sodium or potassium EDTA), ethylenedi preferably a buffer solution. Polar lipid(s), corticosteroid and aminetriacetic acid and diethylenetriaminepentaacetic acid antihistamine (and excipients if and When employed) may be (DTPA). It is also possible to use other agents that protect the added to the aqueous medium in any order during step (a). composition of the invention and, in particular, any unsatur [0077] Preferably the pH of the preparation is adjusted, for ated fatty acid residues that may be present therein, from example prior to the homogenisation step (b) above, to a oxidation. Preferred chelating agents include EDTA and salts desired value Within the range of from about pH 4 to about pH thereof. 8, preferably from about pH 5 to about pH 7, by adding an acid [0068] The composition of the invention can comprise one or a base (e.g. hydrochloric acid and/ or sodium hydroxide at or more preservatives. Examples of common preservatives an appropriate concentration (e. g. lM)). US 2014/0065203 A1 Mar. 6, 2014

[0078] Water, saline or buffer solution may be added, for sWell to form liposomes. In other cases, if any active ingre example prior to the homogenisation step (b) above and/or dient is signi?cantly insoluble in Water and/or phospholipid, after the pH adjusting step mentioned above, to the prepara it may be necessary to dissolve it and the phospholipid in an tion to obtain a desired ?nal batch volume. organic solvent prior to addition of the aqueous phase. Again, [0079] Solutions/liquids may be purged With nitrogen or organic solvent may be removed (eg in vacuo) prior to argon at a suitable stage in the above process, if and as addition of the aqueous phase. appropriate. [0088] The compositions of the invention are useful in the [0080] In the context of the present invention, a lipid may treatment of any indication for Which, the relevant active be said to be sWellable in aqueous media if, When placed in ingredient(s) is/ are knoWn to be effective, for example those contact With such a medium, it sWells to a measurable degree. speci?cally listed for those ingredients in question in Martin [0081] The formation of the liposomes of the invention may dale “The Complete Drug Reference”, 34”’ Edition, Royal be facilitated by the spontaneous sWelling of the polar lipid in Pharmaceutical Society (2005). Water forming a lamellar liquid crystalline phase having a [0089] According to a further aspect of the invention, there maximum Water content of about 35% by Weight or higher is provided a method for the treatment of rhinitis, of asthma depending on the nature of the polar lipid. Depending on the and/or of COPD, comprising the administration of a pharma lipid or lipid mixture used and other conditions, spontaneous cologically-effective amount of a composition of the inven formation of liposomes may be achieved When excess Water is tion to a person suffering from or susceptible to that disorder. added to this lamellar phase. If spontaneous formation is not [0090] For the avoidance of doubt, by “treatment” We achieved, the formation of liposomes may be accomplished include the therapeutic treatment, as Well as the symptomatic by the mechanical dispersion step (i.e. the homogenisation treatment, the prophylaxis, or the diagnosis, of a condition. step (b) of the above process) of the lamellar liquid-crystal [0091] Although compositions of the invention may be line phase in excess Water. administered by any knoWn route, including parenterally, [0082] Homogenisation/dispersion methods include vigor topically and/or perorally, they may normally be to adminis ous mechanical mixing or high speed homogenisation, for tered transmucosally and, more particularly, nasally, ocularly instance by means of an Ultra Turrax® (Jankel & Kiihnke, and pulmonarily. For example, compositions of the invention Germany). Shaking, vortexing and rolling may also be per may be administered by Way of a nasal spray, nasal drops formed as part of the homogenisation step of the above pro and/or eye drops. It is also possible to administer composi cess. tions of the invention as a ?ne mist to the lungs by nebuliZa [0083] A homogeneous siZe distribution of the liposomes tion. For nasal administration, any state-of-the-art device of the invention may be desirable and may be obtained by suitable for producing sprays of aqueous liposomal disper extrusion through a membrane ?lter, such as one made of sions may be used. polycarbonate, With a pore siZe of about 100 nm. Membrane [0092] Such formulations may be prepared in accordance ?lters may be procured from Avestin Inc., Canada. With standard and/or accepted pharmaceutical practice. [0084] A reduced average liposome siZe and narroWed lipo [0093] Wherever the Word “about” is employed herein in some siZe distribution may preferably also be obtained When the context of dimensions (e.g. pH values, siZes, tempera the liposomal dispersion is subjected to high-pressure tures, pressures, etc.) and amounts (e.g. amounts, Weights homogenisation With a suitable homogeniser (Rannie APV, and/or concentrations of individual constituents in a compo type 7.30VH, RannieAS, Denmark) at, for example, betWeen sition or a component of a composition, proportions of active about 300 bar and about 1000 bar, such as betWeen about 400 ingredient(s) inside/outside the liposomal structures, abso bar and about 900 bar, eg about 500 to about 800 bar for lute doses of active ingredient(s), etc.), it Will be appreciated betWeen about 4 and about 8 (eg 7, such as 6) cycles. that such variables are approximate and as such may vary by [0085] We have found that the presence of certain active 10%, for example 15% and preferably 12% (eg 11%) from ingredients (e.g. cetiriZine) may result in a reduction of lipo the numbers speci?ed herein. some siZe. Smaller liposomes are generally advantageous [0094] The compositions of the invention, and the above because they are more stable physically and, due to their mentioned process that may be employed for their prepara higher surface area/volume ratio, are more easily resorbed by tion, have the advantages that are mentioned hereinbefore. In the mucosa. particular, compositions of the invention may reduce the inci [0086] We prefer that the diameter of liposomes in compo dence of inconvenient side-effects (and in particular irrita sitions of the invention is less than about 200 nm (eg tion) that are often observed with eg nasally-administered between about 40 to about 100 nm), as measured by, for formulations. example, laser diffraction or dynamic light scattering. [0095] Compositions of the invention are easy to manufac [0087] Furthermore, the above-mentioned process for the ture and enable the production of liposomal-based formula preparation of compositions of the invention does not nor tions that are in a ready-to-use form, avoiding the need for mally require conventional treatment With organic solvents reconstitution prior to administration. such as chloroform or dichloromethane. HoWever, it may be [0096] Compositions of the invention may also have the appropriate and/or necessary to treat lipids and/or corticos advantage that they may be prepared using established phar teroids With organic solvent prior to the addition of, or addi maceutical processing methods and employ materials that are tion of them to, the aqueous solvent. For example, the lipids approved for use in foods or pharmaceuticals or of like regu and/ or corticosteroids may be dissolved in an organic solvent latory status. or solvent mixture. The solution may then be deposited on the [0097] Compositions of the invention may also have the surfaces of a round-bottomed ?ask as the solvent is removed advantage that they may be more ef?cacious than, be less by rotary evaporation under reduced pressure. An excess vol toxic than, be longer acting than, be more potent than, pro ume of aqueous buffer containing drug(s) may then be added duce feWer side effects than, be more easily absorbed than, to the dry thin ?lm of lipids, Which may then be alloWed to and/ or have a better pharmacokinetic pro?le than, and/ or have US 2014/0065203 A1 Mar. 6, 2014

other useful pharmacological, physical, or chemical proper -continued ties over, pharmaceutical compositions known in the prior art, Whether for use in the treatment of in?ammatory disorders Ingredient Quantity such as rhinitis, asthma and/or COPD, or otherWise. Citric acid, anhydrous 19.2 mg [0098] The invention is illustrated by Way of the following Sodium hydroxide, solid (NaOH) 8.4 mg examples. 1M NaOH and/or 1M HCl to pH 5.5 Puri?ed Water to 1 mL [0099] General Procedure. [0100] For Weights and volumes reference is made to the tables beloW. A buffer solution is prepared by dissolving the EXAMPLE 3 applicable buffer salts in 160 mL Water (80% of the total batch volume) in a 200 mL volumetric ?ask. The Weighed amounts [0104] of applicable excipients are added and dissolved by stirring With a magnetic stirrer. The Weighed amount of the relevant antihistamine is added and dissolved by stirring. Appropriate phospholipid(s), such as Lipoid S100 (and DMPC (if Ingredient Quantity employed)) are separately Weighed, mixed and added to the Loratadine 1.0 mg solution. Finally, the Weighed amount of the relevant corti Budesonide 320 pg costeroid is added and stirring is continued until a Well dis Lipoid S100 35.0 mg Benzalkonium chloride 0.2 mg persed suspension has formed; the desired pH is adjusted With Citric acid, anhydrous 19.2 mg 1.0 M NaOH and/or 1.0 M HCl. The volume of the prepara Sodium hydroxide, solid (NaOH) 8.4 mg tion is then brought to the ?nal batch volume of 200 mL. The 1M NaOH and/or 1M HCl to pH 5.0 preparation is transferred to a high pressure homogeniser Puri?ed Water to 1 mL (Rannie APV, type 7.30 VH, Rannie AS, Denmark) and homogenised at 800 bar for 7 cycles. Aliquots of the thus obtained composition are removed from the collecting vessel EXAMPLE 4 and transferred to glass vials. [0105] [0101] The above procedure Was employed in order to pre pare ?nal compositions as outlined in Examples 1 to 4 beloW. Where appropriate, the quantities of the components Were scaled up appropriately (eg in the case of Examples 1 to 4, Ingredient Quantity multiplied by 200). The procedures for Examples 5 and 6 are Loratadine 1.0 mg described separately beloW. Fluticasone propionate 125 pg DMPC 8.05 mg EXAMPLE 1 Lipoid S100 26.95 mg Citric acid, anhydrous 19.2 mg Sodium hydroxide, solid (NaOH) 8.4 mg [01 02] 1M NaOH and/or 1M HCl to pH 5.0 Puri?ed Water to 1 mL

Ingredient Quantity [0106] The commercially available nasal antihistamine aZelastine (registered trademarks including AZelvin®, Cetirizine dihydrochloride 11.1 mg Budesonide 320 pg AZosin®, Astelin®, Lastin®, and Rhinolast®) Was formu DMPC 8.05 mg lated using the quantities and steps outlined beloW. Lipoid S100 26.95 mg BHT 0.02% EXAMPLE 5 Benzalkonium chloride 0.2% Citric acid, anhydrous 19.2 mg [0107] 1. 160 mL of aZelastine solution for nasal adminis Sodium hydroxide, solid (NaOH) 8.4 mg tration (Lastin®) containing 0.9 mg/mL aZelastine Was 1M NaOH and/or 1M HCl to pH 5.5 Puri?ed Water to 1 mL transferred to a 200 mL volumetric ?ask. [0108] 2.7 g of soy bean phospholipid (Lipoid S100, Lipoid GmbH, Germany) Was added. [0109] 3. 64 mg of budesonide Was added and stirring Was EXAMPLE 2 continued until a Well dispersed suspension had formed (overnight). [01 03] [0110] 4. The volume Was brought to 200 mL by the addi tion of more aZelastine solution (see step 1 above). [0111] 5. The pH Was checked. Ingredient Quantity [0112] 6. The solution Was homogenised for 7 cycles at 800 bar as described in the general procedure above. Cetirizine dihydrochloride 11.1 mg Fluticasone propionate 125 pg DMPC 8.05 mg EXAMPLE 6 Lipoid S100 26.95 mg BHT 0.02% [0113] The general procedure described in Example 5 Benzalkonium chloride 0.2% above Was folloWed, except that, in place of step (3), 25 mg of ?uticasone propionate Was added in place of the budesonide. US 2014/0065203 A1 Mar. 6, 2014

1. A homogeneous pharmaceutical composition compris thixene, pipinhydrinate, promethaZine, propiomaZine, ing quifenadine, rupatadine, , terfenadine, thenyl an antihistamine, diamine, thiethylperaZine, , tolpropamine, tri a corticosteroid, methobenZamine, tripelennamine, triprolidine, tritoqualine, a phospholipid selected from the group consisting of phos loratadine, aZelastine, fexofenadine, levocetiriZine, cetiriZ phatidylcholine, phosphatidylglycerol, phosphatidyli ine, and a pharmaceutically-acceptable salt of any of these nositol, phosphatidic acid, phosphatidylserine, dilau compounds. rylphosphatidylcholine, dipalmitoylphosphatidylcholine, dilaurylphosphati 8. (canceled) dylglycerol, dimyristolphosphatidylglycerol, dio 9. The composition as claimed in claim 7, Wherein the leoylphosphatidylglycerol, dioleoylphosphatidylcho antihistamine is cetiriZine and the salt is a chloride salt, a line, dimyristolphosphatidylcholine, hydrochloride salt, a cetiriZing dinitrate, a cetiriZine dihydro dioleoylphosphatidylcholine, dimyristolphosphatidyl chloride, or a nitrate salt. choline and mixtures thereof; 10.-12. (canceled) a polar lipid liposome; a pharmaceutically-acceptable aqueous carrier, 13. The composition as claimed in claim 1 Wherein the a pharmaceutically-acceptable phosphate, citrate or corticosteroid is selected from the group consisting of acetate buffer capable of providing a pH of from about alclometasone, beclometasone, betamethasone, budesonide, pH 4 to about pH 8; ciclesonide, clobetasol, clobetasone, de?aZacort, deprodone, an antioxidant selected from the group consisting of l-to dexamethasone, di?ucortolone, ?uocinolone, etiprednol, copherol, ascorbic acid, butylated hydroxyanisole, buty ?unisolide, ?uocinonide, ?uocortolone, ?uprednidene, ?uo lated hydroxytoluene, citric acid, fumaric acid, malic rometholone, ?uticasone, halcinonide, hydrocortisone, KSR acid, monothioglycerol, propionic acid, propyl gallate, 592, loteprednol, methylprednisolone, mometasone, pred sodium ascorbate, sodium bisul?te, sodium met nisolone, rimexolone, triamcinolone, budesonide, ciclesonide, ?uticasone, triamcinolone, mometasone, and a abisul?te, potassium metabisul?te, sodium sul?te, tar pharmaceutically-acceptable salt of any of these compounds. taric acid, vitamin E and mixtures thereof; a chelating agent selected from the group consisting of 14.-17. (canceled) ethylenediaminetetraacetic acid, ethylenediaminetri 18. The composition as claimed in claim 1, Wherein the acetic acid, diethylenetriaminepentaacetic acid and salts phospholipid comprises one that is represented by the general thereof; formula I, a preservative selected from the group consisting of ben Zalkonium chloride, benZoic acid, butylated hydroxya nisole, butylparaben, chlorbutanol, ethylparaben, meth ylparaben, propylparaben, phenoxyethanol and phenylethyl alcohol; and a viscosity-increasing agent selected from the group con sisting of polyethyleneglycol, crosslinked polyvinylpyr rolidone and hydroxypropylmethyl cellulose. 2. (canceled) 3. The composition as claimed in claim 1, Wherein the pH range is about pH 5 to about pH 7. 4. (canceled) 5. The composition as claimed in claim 1, Wherein the buffer is disodium phosphate, dipotassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phos wherein R1 and R2 independently represent a saturated or phate, phosphoric acid plus base, sodium citrate, citric acid unsaturated, branched or straight chain alkyl group having plus base, sodium acetate or acetic acid plus base. betWeen 7 and 23 carbon atoms and R3 represents an amide or 6. (canceled) ester bonding group, Wherein the amide or ester bonding 7. The composition as claimed in claim 1, Wherein the group is iCH2iCH(OH)4CH2OH, 4CH24CH2iN antihistamine is selected from the group consisting of acriv (CH3)3, iCH2iCH2iNH2, iH or %H2%H(NH2)i astine, alimemaZine, anataZoline, , aZatadine, COOH. aZelastine, bamipine, bepotastine, bromaZine, bromophe 19.-29. (canceled) niramine, bucliZine, carbinoxamine, cetiriZine, chlorocycliZ ine, chloropyramine, chlorophenamine, cinnariZine, clemas 30. The composition as claimed in claim 74, Wherein the tine, clemiZole, clociniZine, cycliZine, cyproheptadine, glycosphingolipid is selected from the group consisting of a deptropine, desloratadine, , dimenhy monoglycosylsphingoid, an oligoglycosylsphingoid, an oli drinate, dimetindene, , diphenhydramine, goglycosylceramide, a monoglycosylceramide, a sialogly piphenylpyraline, doxylamine, ebastine, e?etiriZine, cosphingolipid, a uronoglycosphingolipid, a sulfoglycosph embramine, emedastine, epinastine, fexofenadine, ?unariZ ingolipid, a phosphoglycosphingolipid, a ine, homochlorocycliZine, , isothipendyl, levo phosphonoglycosphingolipid, a ceramide, a monohexosylce carbastine, levocetiriZine, loratadine, mebhydroline, mecloZ ramide, a dihexosylceramide, a sphingomyelin, a lysosphin ine, mepyramine, mequitaZine, methdilaZine, miZolastine, gomyelin, a sphingosine, a sphingomyelin and a mixture niapraZine, olopatadine, , oxomemaZine, pemiro thereof. last, phenindamine, , phenyltoloxamine, pime 31.-33. (canceled) US 2014/0065203 A1 Mar. 6, 2014

34. The composition as claimed in claim 1, wherein the 56. The process as claimed in claim 46, Wherein the amount of phospholipid in the composition is from about 17 homogenisation step and/or siZe-reduction step comprises mg/mL to about 70 mg/mL or about 20 mg/mL to about 40 high-pressure homogenisation. mg/mL. 57.-70. (canceled) 35.-45. (canceled) 71. A method for the treatment of rhinitis, of asthma and/or 46. A process for preparing a composition as claimed in of chronic obstructive pulmonary disease comprising the claim 1, Which process comprises: administration of an effective amount of a composition as (a) mixing together, in an aqueous medium, a corticoster claimed in claim 1, to a person suffering from or susceptible oid, an antihistamine and a polar lipid, or a mixture of to that disorder. polar lipids, that is/are sWellable in aqueous media; and 72.-73. (canceled) (b) homogenising the preparation. 74. A homogeneous pharmaceutical composition compris 47.-50. (canceled) ing 51. The process as claimed in claim 46, Wherein the aque an antihistamine, ous medium is purged With nitrogen and/ or argon. a corticosteroid, 52. The process as claimed in claim 51, Wherein the lipid(s) a glycolipid or a mixture of glycolipids comprising a diga and/or corticosteroid is/are pre-treated With an organic sol lactosyldiacylglycerol, glycosphingolipid or glycoph vent. osphatidylinositol; 53. The process as claimed in claim 52, Wherein the a pharmaceutically-acceptable aqueous carrier, homogenisation step (b) comprises vigorous mechanical a pharmaceutically-acceptable phosphate, citrate or mixing, high speed homogenisation, shaking, vortexing and/ acetate buffer capable of providing a pH of from about or rolling. pH 4 to about pH 8; 54. The process as claimed in claim 53, Which comprises an an antioxidant; additional liposome siZe-reduction step. a chelating agent; 55. The process as claimed in claim 54, Wherein the siZe a preservative; and reduction step comprises extrusion through a membrane ?l a viscosity-increasing agent. ter. * * * * *