US 9,717,723 B2  18  17  tamine  ethylenediamine  derivatives  (bromphenifamine,  diphenhydramine ); Anti-protozoa!: quinolones (iodoquinol);  amidines (pentamidine );  antihelmintics (pyrantel); anti› schistosomal drugs  ( oxaminiquine );  antifungal triazole  derivatives (fliconazole, itraconazole, ketoconazole, micon› azole ); antimicrobial cephalosporins ( cefazolin, cefonicid,  cefotaxime, ceftazimide, cefuoxime); antimicrobial beta› lactam derivatives (aztreopam, cefmetazole, cefoxitin); anti› microbials of erythromycine group ( erythromycin, azithro› mycin,  clarithromycin,  oleandomycin);  penicillins  (benzylpenicillin,  phenoxymethylpenicillin,  cloxacillin,  methicillin, nafcillin, oxacillin, carbenicillin); tetracyclines;  other antimicrobial antibiotics, novobiocin, spectinomycin,  vancomycin; antimycobacterial drugs: aminosalicycic acid,  capreomycin, ethambutol, isoniazid, pyrazinamide, rifabu› tin, rifampin, clofazime; antiviral adamantanes: amantadine,  rimantadine; quinidine derivatives: chloroquine, hydroxy› chloroquine, promaquine, qionone; antimicrobial qionolo› nes: ciprofloxacin, enoxacin, lomefloxacin, nalidixic acid,  norfloxacin, ofloxacin; sulfonamides; urinary tract antimi› crobials:  methenamine,  nitrofurantoin,  trimetoprim;  nitroimidazoles:  metronidazole;  cholinergic  quaternary  ammonium compounds (ambethinium, neostigmine, phys› ostigmine); anti-Alzheimer aminoacridines (tacrine); anti› Parkinsonal drugs (benztropine, biperiden, procyclidine, tri› hexylhenidyl);  anti-muscanmc  agents  (atropine,  hyoscyamine, scopolamine, propantheline ); adrenergic dop› amines (albuterol, dobutamine, ephedrine, epinephrine, nor› epinephrine, isoproterenol, metaproperenol, salmetrol, terb› utaline ); ergotamine derivatives; myorelaxants or curane  series; central action myorelaxants; baclophen, cycloben› zepine, dentrolene; nicotine; beta-adrenoblockers (acebutil,  amiodarone ); benzodiazepines ( ditiazem); antiarrhythmic  drugs ( diisopyramide, encaidine, local anesthetic series› procaine, procainamide, lidocaine, flecaimide ), quinidine;  ACE inhibitors: captopril, enelaprilat, fosinoprol, quinapril,  ramipril; antilipidemics: fluvastatin, gemfibrosil, HMG-coA  inhibitors (pravastatin); hypotensive drugs: clonidine, gua› nabenz, prazocin, guanethidine, granadril, hydralazine; and  non-coronary vasodilators: dipyridamole.  According to the present invention, the entity contained in  the liposome composition of the present invention can also  be a pre-entity, e.g., a pro-drug or an agent that is capable of  being converted to a desired entity upon one or more  conversion steps under a condition such as a change in pH  or an enzymatic cleavage of a labile bond. Such conversion  may occur after the release of the pro-drug from the lipo› some interior at the intended site of the drug/liposome  action. However, the pre-entity can be converted into the  desired active entity inside the liposomes of the present  invention prior to the use of the liposomes as a delivery  vehicle, e.g., administration to a patient. For example, an  entity can be modified into a pre-entity so that it is easier to  be loaded into the liposomes and then it can be converted  back into the desired entity once it is inside the liposomes of  the present invention. In this manner, according to the  present invention, the entities that are generally not ame› nable to "active", "remote" or other gradient-based loading  methods, can be effectively loaded into liposomes, e.g., into  the liposome interior space, in their native, unmodified form.  Globally cationic compounds, that is, compounds capable  of attaining a net positive ionic charge under the liposome  loading conditions, especially the compounds containing a  titratable amine, are known to effectively load into lipo› somes exhibiting transmembrane ion gradients.  If an entity  of interest is an organic compound and is not a globally  cationic compound having a titratable amine, a derivative  According to the present invention, the liposomes con› tained in the liposome composition of the present invention  can also be targeting liposomes, e.g., liposomes containing  one or more targeting moieties or biodistribution modifiers  on the surface of the liposomes. A targeting moiety can be  any agent that is capable of specifically binding or interact› ing with a desired target. In one embodiment, a targeting  According to the present invention, the liposomes con› tained in the liposome composition of the present invention  can be any liposome known or later discovered in the art. In  general, the liposomes of the present invention can have any  liposome structure, e.g., structures having an inner space  sequestered from the outer medium by one or more lipid  bilayers, or any microcapsule that has a semi-permeable  membrane with a lipophilic central part where the mem› brane sequesters an interior. A lipid bilayer can be any  arrangement of amphiphilic molecules characterized by a  hydrophilic part (hydrophilic moiety) and a hydrophobic  part (hydrophobic moiety). Usually amphiphilic molecules  in a bilayer are arranged into two dimensional sheets in  which hydrophobic moieties are oriented inward the sheet  while hydrophilic moieties are oriented outward. Amphiphi› lic molecules forming the liposomes of the present invention  can be any known or later discovered amphiphilic mol- ecules, e.g., lipids of synthetic or natural origin or biocom› patible lipids. Liposomes of the present invention can also  be formed by amphiphilic polymers and surfactants, e.g.,  polymerosomes and niosomes. For the purpose of this  disclosure, without limitation,  these liposome-forming  materials also are referred to as "lipids".  thereof having the requisite ionic properties can be prepared  by a suitable modification, e.g., according to the methods  described in Woodle et al., in WO 96/25147. For example,  an amine group can be introduced by esterification of a  hydroxyl group of the entity with an amino acid. Alterna› tively, a hydrophobic group can be introduced into a water› soluble compound to aid in its partition into the liposome  membrane and subsequent traversing of the membrane to the  intraliposomal compartment, i.e., inside the liposomes.  Another useful modification to create a liposome-loadable  pre-entity is the formation of a carbonyl group adduct, e.g.,  a hydrazone, an oxime, an acetal, or a ketal. A modified  amino-containing group can be hydrolyzed or otherwise  chemically split from the modified compound after the  loading of the modified compound into the liposomes  according to the present invention. Typical processes to  intraliposomally regenerate the entity from a pre-entity are  hydrolysis, photolysis, radiolysis, thiolysis, ammonolysis,  reduction, substitution, oxidation, or elimination. These pro- cesses can be effected, without limitation, by the change of  pH or by an enzymatic action. For example, paclitaxel or  docetaxel, a non-ionic entities, are converted into their  2’-(  diethylaminopropionyl)- or T-( diethylaminopropionyl)  esters, which are weak bases (pre-entities). After loading  into the liposomes by any known method, including, without  limitation, "active", "remote", "transmembrane-gradient› based" or "solubility gradient based" methods, and/or the  methods of the present invention, the intraliposomal 2’› ( diethylaminopropionyl)-paclitaxel is converted into origi- nal paclitaxel by stimulating its hydrolysis through the  increase of pH to above pH 7 .0. Thus, a liposome encapsu› lating a neutral taxane molecule within its interior space is  obtained with the drug/lipid ratio of over 0.05 mole per mole  of the liposome lipid, without the help of hydrophilic  covalent modifications of the taxane molecule ( e.g. by  attachment of PEG), cyclodextrine taxane complexes, or  taxane-solubilizing, micelle-forming surfactants. 