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US 2006/0165744 A1 Jamil Et Al US 2006O165744A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0165744 A1 Jamil et al. (43) Pub. Date: Jul. 27, 2006 (54) COMBINATION LIPOSOMAL Related U.S. Application Data FORMULATIONS (60) Provisional application No. 60/472.664, filed on May (75) Inventors: Haris Jamil, Libertyville, IL (US); 22, 2003. Provisional application No. 60/495,260, Imran Ahmad, Wadsworth, IL (US); filed on Aug. 13, 2003. Zafeer Ahmad, Gurnee, IL (US); Gopal Anyarambhatla, Decatur, IL Publication Classification (US) (51) Int. Cl. AOIN 25/00 (2006.01) Correspondence Address: A 6LX 9/27 (2006.01) LEYDIG VOIT & MAYER, LTD CI2N 5/88 (2006.01) TWO PRUDENTIAL PLAZA, SUITE 4900 (52) U.S. Cl. ........................... 424/405; 424/450: 435/.458 18O NORTH STETSON AVENUE CHICAGO, IL 60601-6780 (US) (57) ABSTRACT (73) Assignee: NeoPharm, Inc, Lake Forest, IL (US) The present invention provides a composition comprising a physiologically acceptable carrier and two or more agents encapsulated in a liposome, wherein the combination of the (21) Appl. No.: 10/558,159 two or more agents possess the following properties: (1) cytotoxicity to tumor cells, (2) nutritional properties, (3) use in application to nails, hair, skin or lips or (4) activity against (22) PCT Filed: May 22, 2004 parasites and insects. The invention also provides a method of making such a composition. The invention further pro vides a method of treating cancer when the combination of (86). PCT No.: PCT/USO4/16413 the two or more agents is cytotoxic to tumor cells. US 2006/01 65 744 A1 Jul. 27, 2006 COMBINATION LIPOSOMAIL FORMULATIONS more agents (e.g., drugs or other active agents) is cytotoxic to tumor cells, and a physiologically acceptable carrier. CROSS REFERENCE TO RELATED These and other advantages of the invention, as well as APPLICATIONS additional inventive features, will be apparent from the 0001. This application claims priority to U.S. Provisional description of the invention provided herein. Patent Application 60/472,664, filed May 22, 2003. This application also claims priority to U.S. Provisional Patent DETAILED DESCRIPTION OF THE Application 60/495,260, filed Aug. 13, 2003. The disclo INVENTION Sures of these two applications are incorporated in their 0006 The invention is directed to a composition com entireties herein by reference thereto. prising a physiologically acceptable carrier and two or more agents (e.g., drugs or other active agents) encapsulated into FIELD OF THE INVENTION a liposome. Liposomes are well known in the art as spherical 0002 This invention pertains to a composition compris drug-delivery vehicles composed of a lipid bilayer (typically ing two or more agents (e.g., drugs or other active agents) a phospholipid bilayer) Surrounding an internal aqueous encapsulated into a liposome. cavity (see, e.g., U.S. Pat. No. 6,146,659 and Published U.S. Patent Application No. 2003/0035830A1). The liposome BACKGROUND OF THE INVENTION according to the invention can be prepared using any Suit able method known in the art. The chosen method will 0003. The treatment of cancer has progressed signifi depend on the nature of the drugs or active agents (e.g., cantly with the development of drugs that more efficiently water-soluble, water-insoluble, or hydrophobic) encapsu target and kill cancer cells. Many cancer types, however, lated by the liposome. Standard methods for preparing manifest as multifactorial diseases, which often require a liposomes are known to those skilled in the art, such as those multimodal therapeutic approach. In this respect, clinicians described in, for example, U.S. Pat. Nos. 5,424,073, 5,648, have realized limited success with the administration of a 090, and 6,146,659. In this regard, liposome preparation single drug to treat a particular type of cancer. Indeed, both typically involves dissolving or dispersing lipophilic lipo preclinical and clinical studies have revealed that chemo some-forming ingredients, such as those described herein, in therapy regimens employing two or more anticancer drugs a suitable solvent or combination of solvents and dried. produce a synergistic effect on therapeutic efficacy as com Suitable solvents include any non-polar or slightly polar pared to administration of each drug individually (see, e.g., solvent, such as t-butanol, ethanol, methanol, chloroform, or Damon et al., Cancer Invest., 4, 421-44 (1986), Caponigro acetone, that can be evaporated without leaving a pharma et al., Anticancer Drugs, 12, 489-97 (2001), and U.S. Pat. ceutically unacceptable residue. Drying can be by any No. 6,469,058). As a result, current chemotherapy protocols Suitable means such as by lyophilization. Hydrophilic ingre typically involve concurrent administration of two or more dients can be dissolved in polar solvents, including water. anticancer drugs to a patient ("combination chemotherapy'). 0007 Liposomes typically are prepared by mixing the 0004 Although combination chemotherapy has proven to dried lipophilic ingredients with a polar, hydrophilic solu be more effective in killing cancer cells than pharmaceuti tion, preferably an aqueous Solution. Suitable solutions cals containing only one active agent, each type of therapy include water or aqueous solutions containing pharmaceu has inherent limitations. Many anticancer drugs exhibit an tically acceptable salts, buffers, or their mixtures. The lipo extremely low solubility in water, making it difficult to Somes are hydrated by dispersing the lipid in the aqueous prepare aqueous formulations of a particular drug. More Solution with vigorous mixing. Any method of mixing can over, repeated administrations of an anticancer drug can be used provided that the chosen method induces sufficient produce multidrug resistance in the treated patient, thereby shearing forces between the lipid film and polar solvent to reducing drug efficacy over time. The dose-limiting toxicity strongly homogenize the mixture and form the desired of certain drugs also limits their therapeutic potential. Thus, complexes. For example, mixing can be by Vortexing, mag formulations Suitable for combination chemotherapy are netic stirring, and/or Sonicating. Where multilamellar lipo needed that can overcome the solubility problems associated Somes are desired, they can be formed simply by Vortexing with anticancer drugs, reduce their toxicity, and enhance the solution. Where unilamellar liposomes are desired, a their efficacy. Sonication, filtration or extrusion step is included in the process. BRIEF SUMMARY OF THE INVENTION 0008. Where active agents are included in the liposomes, 0005 The invention provides a composition comprising a they can be dissolved or dispersed in a suitable solvent and physiologically acceptable carrier and two or more agents added to the liposome mixture prior to mixing. Typically, (e.g., drugs or other active agents) encapsulated into a hydrophilic active agents are encapsulated into liposomes by liposome, wherein the combination of the two or more hydrating the dry lipid film with an aqueous solution of the agents possess the following properties: (1) cytotoxicity to active agent (also referred to as simple encapsulation). In tumor cells, (2) nutritional properties, (3) use in application this manner, the active agent is passively encapsulated in the to nails, hair, skin or lips or (4) activity against parasites and interlamellar spaces of the liposome. Alternatively, hydro insects. The invention also provides a method of making philic, water-soluble active agents can be encapsulated in Such a composition. The invention further provides a method liposomes by a reverse loading technique. This method of treating cancer, comprising administering to the host a involves the dispersal of neutrally charged drugs or other composition comprising a therapeutically effective amount active agents in the aqueous phase of a liposome prepara of a liposome comprising two or more agents (e.g., drugs or tion, which allows the uncharged drugs or other active other active agents), wherein the combination of the two or agents to permeate into liposomes via the lipid bilayer. The US 2006/01 65 744 A1 Jul. 27, 2006 pH of the liposome solution is adjusted to create a charge on Solvents can be used, such as ethanol, methanol, chloroform, the active agent, rendering the active agent unable to pass or acetone. In accordance with the present invention, sepa back through the bilayer and into the external medium, rate Solutions of cardiolipin and one or more drugs or other thereby entrapping the active agent in the liposome. Lipo active agents can be mixed, or, alternatively, cardiolipin and philic active agents (e.g., hydrophobic drugs or other active one or more drugs or other active agents can be dissolved agents or water-insoluble drugs or other active agents) can together in the same solution, as desired. be incorporated into liposomes by partitioning. In this regard, the active agent is dissolved along with the lipophilic 0013 The inventive composition preferably comprises ingredients in a suitable nonpolar solvent. The resulting liposomes containing cardiolipin in combination with other solution can either be dried and mixed with a polar solvent lipophilic agents. Suitable lipophilic agents include pharma as described above, or directly added to the aqueous phase ceutically acceptable synthetic, semi-synthetic (modified and extracted. In this manner, the active agent is incorpo natural) or naturally occurring compounds having a hydro rated into the lipid portion of the liposome
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