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In disodium salt of cromolyn; |
Background of the Invention The present invention is directed to liposomal cromolyn formulations comprising cromolyn and neutral PH cholesterol hydrogen succinate lipids. This invention specifically discloses formulations wherein the lipid portion of the liposome comprises lipids such as neutralized cholesterol hydrogen succinate known as cholesterol hemisuccinate (CHS), saturated phospholipids such as hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC) or lipid mixtures such as a HSPC-cholesterol, DPPC-cholesterol or dimyristoylphosphatidylcholine (DMPC)-cholesterol. The term cromolyn as used herein includes all structural analogs and functional derivatives of cromolyn as disclosed in U.S. Patent No. 3,419,578. Functional derivatives of cromolyn include its salts, esters and amides, in particular the disodium salt of cromolyn e.g. disodium cromoglycate or cromolyn sodium. cromolyn, whose chemical names include 5,5' -[(2-Hydroxy-1,3-propanediyl)bis-(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylic acid]; 5,5'. -[(2-hydroxytrimethylene)dioxy]bis(4-oxo-4H-1-benzopyran-2-carboxylic acid); 5,5'. -(2-hydroxytrimethylenedioxy)bis(4-oxochromene-2-carboxylic acid); 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane;. 1,3-di(2-carboxy-oxochromen-5-yloxy)propan-2-ol; and cromoglycic acid, has the following chemical structure: / Its method of preparation is described in U.S. Patent No. 3,419,578. cromolyn is knob to be useful for the treatment of allergic conditions, e.g. asthma, hay fever and conjunctivitis of allergic origin, e.g. vernal kerato conjunctivitis and allergic rhinitis. Other disclosed uses of disodium cromoglycate include the treatment of viral infections, the treatment of gastro-intestinal diseases e.g. ulcerative colitis and food allergies and the treatment of skin conditions, e.g. chronic dermatoses such as eczemas, psoriasis, dermatitis and chronic skin ulcers. Liposomes are completely closed lipid bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single bilayer membrane) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer). The bilayer is composed of two lipid monolayers having a hydrophobic 'tail' region and a hydrophilic 'head' region. The structure of the membrane bilayer is such that the hydrophobic (nonpolar) 'tails' of the lipid monolayers orient toward the center of the bilayer while the hydrophilic 'head' orient towards the aqueous phase. The original liposome preparation of Bangham, et al. (J. Mol. Biol. , 1965, 12:238-252) involves suspending phospholipids in an organic solvent which is then evaporated to dryness leaving a phospholipid film on the reaction vessel. Next, an appropriate amount of aqueous phase is added, the mixture is allowed to 'swell,' and the resulting liposomes which consist of multilamellar vesicles (MLVs) are dispersed by mechanical means. This technique provides the basis for the development of the small sonicated unilamellar vesicles described by Papahadjopoulos et al. (Biochim. Biophys. Acta. , 1968, 135:624-638), and large unilamellar vesicles. Unilamellar vesicles may be produced using an extrusion apparatus by a method described in Cullis et al., PCT Application No. WO87/00238, published January 16, 1986, entitled 'Extrusion Technique for Producing Unilamellar Vesicles' incorporated herein by reference. Vesicles made by this technique, called LUVETS, are extruded under pressure through a membrane filter. Vesicles may also be made by an extrusion technique through a 200 nm filter. Such vesicles are known as VET2sub;0?S. Another class of liposomes that may be used in the present invention are those characterized as having substantially equal lamellar solute distribution. This class of liposomes is denominated as stable plurilamellar vesicles (SPLV) as defined in U.S. Patent No. 4,522,803 to Lenk, et al., monophasic vesicles as described in U.S. Patent No. 4,588,579 to Fountain, et al. and frozen and thawed multilamellar vesicles (FATMLV) wherein the vesicles are exposed to at least one freeze and thaw cycle; this procedure is described in Bally et al., PCT Publication No. WO87/00043, January 15, 1987, entitled 'Multilamellar Liposomes Having Improved Trapping Efficiencies'. cromolyn (e.g., sodium cromoglycate) liposomal formulations are known in the art. European Patent Publication No. 0 084 898 published August 3, 1983, discloses pharmaceutical compositions comprising liposomes and sodium cromoglycate for treating asthma, hay fever and vernal kerato conjunctivitis. However, liposomal cromolyn compositions having the formulations of the instant invention such as neutral PH CHS lipids or DMPC-Chol or HSPC-Chol lipid mixtures are new. |
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