US 2003.0068365A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0068365A1 Suvanprakorn et al. (43) Pub. Date: Apr. 10, 2003 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME BEADS (60) Provisional application No. 60/327,643, filed on Oct. 5, 2001. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); Tanusin Ploysangam, Bangkok (TH); Publication Classification Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok (51) Int. Cl." .......................... A61K 9/127; A61K 35/78 (TH); Nardo Zaias, Miami Beach, FL (52) U.S. Cl. ............................................ 424/450; 424/725 (US) (57) ABSTRACT Correspondence Address: Law Office of Eric G. Masamori Compositions and methods for administration of active 6520 Ridgewood Drive agents encapsulated within liposome beads to enable a wider Castro Valley, CA 94.552 (US) range of delivery vehicles, to provide longer product shelf life, to allow multiple active agents within the composition, (21) Appl. No.: 10/264,205 to allow the controlled use of the active agents, to provide protected and designable release features and to provide (22) Filed: Oct. 3, 2002 Visual inspection for damage and inconsistency. US 2003/0068365A1 Apr. 10, 2003 COMPOSITIONS AND METHODS FOR toxic degradation of the products, leakage of the drug from ADMINISTRATION OF ACTIVE AGENTS USING the liposome and the modifications of the Size and morphol LPOSOME BEADS ogy of the phospholipid liposome vesicles through aggre gation and fusion. Liposome vesicles are known to be CROSS REFERENCE TO OTHER thermodynamically relatively unstable at room temperature APPLICATIONS and can Spontaneously fuse into larger, leSS Stable altered liposome forms. 0001) This application claims the benefit of U.S. Provi sional Patent Application No. 60/327,643 filed Oct. 5, 2001. 0007 Also adding to the potential instability of lipo Somes in conventional formulations is the pKa. The pKa of FIELD OF INVENTION compounds may be defined by the pH at which concentra tions of both the uncharged and charged forms of the 0002 The present invention relates to compositions and molecules are found. methods for administration of active agents, including but not limited to cosmetic, cosmeceuticals and pharmaceuti 0008 Various schemes have been devised to avoid some cals, to biological organisms in need thereof. More specifi the Stability and limitations of liposome formulations, Such cally, the present invention relates to aggregated or globu as freeze drying of the composition. The freeze dried com lized multiple encapsulations of active agents using position is reconstituted as required for use. conventionally prepared liposomes and aggregating or 0009 What is needed is a liposome formulation that globulizing those liposomes into globules or beads. avoids the disadvantages of pre-existing liposomes formu lations discussed above, that has a longer shelf-life, provides BACKGROUND OF THE INVENTION controlled and increased concentrations of active agents at 0003) When phospholipids and many other amphipathic or near the desired target administration site, allows Segre lipids are dispersed gently in an aqueous medium they gation of different active agents and provides the ability to hydrate and Spontaneously form multilamellar concentric Visually determine if the integrity of the lipoSome has been bilayer vesicles. The lipid bilayers are separated with layers affected by undesired alterations. of the aqueous media. These vesicles are commonly referred to as multilamellar liposomes or multilamellar vesicles and SUMMARY OF THE INVENTION usually have diameters of about 0.2 um to 5 Lim. Sonication 0010. The present invention contemplates the use of of the multilamellar vesicles results in the formation of liposome encapsulated materials made by any conventional smaller unilamellar vesicles with diameters usually in the means and Subsequently, or in addition to the encapsulation range of 20 to 100 nm, containing an aqueous Solution in the process, provides a System to Suspend these liposomes into core. Multivesicular liposomes differ from multilamellar discrete multilamellar vesicles or beads. The multilamellar liposomes in the random, non-concentric arrangement of the vesicles or beads are designed with Surface tensions of chambers within the liposome. Amphipathic lipids can form different Strengths to provide an improved delivery System a variety of Structures other than liposomes when dispersed of a drug or other active agent. The present invention in water, depending on the molar ratio of lipid to water, but provides compositions and methods of administration of at low ratios the liposome is the preferred Structure. globules or beads of liposomal formulations and active 0004. The physical characteristics of liposomes generally agents in predetermined sizes with Similar or different active depend on pH and ionic strength. They characteristically agents, thereby enhancing the use of the drug or active show low permeability to ionic and polar Substances, but at agents in a number of different ways. certain temperatures can undergo a gel-liquid crystalline 0011. Accordingly, the present invention provides a com phase transition dependent upon the physical properties of position and method of administration of active agents the lipids used in their manufacture which markedly alters which, when used in combination with liposomes, enables a their permeability. The phase transition involves a change wider range of vehicles, provides longer life of the product, from a closely packed, ordered Structure, known as the gel provides controlled and increased concentrations of active State, to a loosely packed, less ordered Structure, known as agents at or near the desired target administration Site, the liquid crystalline phase. provides protected and designable release features, allows 0005 Various types of lipids differing in chain length, Segregation of different active agents and allows the con Saturation, and head group have been used in liposomal drug trolled use of the active agent and their visual inspection for formulations for many years, including the unilamellar, damage and consistency. multilamellar and multivesicular liposomes described 0012. In general, the invention comprises a composition above. The major goal of the field is to develop liposomal and method for the administration of beads or globules of formulations for Sustained release of drugs and other com liposomal formulations and active agents. The active agents pounds of interest and to develop liposome formulations include but are not limited to cosmetics, cosmeceuticals and from which the rate of release of the encapsulated material pharmaceuticals. A liposomal Suspension of multilamellar can be controlled. vesicles encapsulating the active agent is prepared by con 0006 Various limitations on the shelf-life and use of ventional methods. The liposomal Suspension is placed into lipoSome compounds exist due to the relatively fragile a physical or physiochemical bonding Solution resulting in a nature of liposomes. Major problems encountered during liposomal first Solution. The resulting liposomal first Solu lipoSome drug Storage in vesicular Suspension are the chemi tion is then aliquoted into a Second Solution containing at cal alterations of the liposome compounds, Such as phos least one inorganic Salt. The at least one inorganic Salt of the pholipids, cholesterols, ceramides, leading to potentially Second Solution comprises 1-2% by weight of the Second US 2003/0068365A1 Apr. 10, 2003 Solution. Upon entry into the Second Solution, the liposomal the group consisting of calcium chloride, calcium Sulfate, first Solution develops a hardened Surface and forms a bead. calcium carbonate, mangesium chloride, magnesiun Sulfate, The beads are then aggregated and washed with an inert barium chloride, or barium Sulfate. In alternate embodi Solution to remove any residual liposomal first Solution and ments, other inorganic Salts may be used in the Second Second Solution. The resulting liposomal beads are now Solution. In the preferred embodiment, the inorganic Salt ready for use. comprises about 1 to 2% by weight of the second solution. 0013 In the preferred embodiment, multiple portions of 0019. In the preferred embodiment, the liposomal first an empty acqueous liposome formulation are lyophilized and Solution is introduced into the inorganic Salt Solution hydrated with a Solution of active agent or other material that through a predetermined orifice which allows for a specific are to be encapsulated resulting in the formation of lipoSome Size or amount of liposomal first Solution to be introduced. multilamellar vesicles containing the active agent or mate In prototype development testing, the types of delivery rials. In the preferred embodiment, the active agent is Systems used included needle injection and disc Spinning. Selected from the group consisting of cosmetics, cosmeceu However, other types of delivery Systems, Such as Spraying, ticals and pharmaceuticals. However, in alternate embodi hydraulic pressure pump, gravitational dipping, pneumatic ment, it may be possible for one skilled in the art to use other pumping or liquidating methods may be used. The means of materials with different therapeutic characteristics. The por bead formation can be achieved by a number of alternative tions of liposome Solution are then Separated or pooled to embodiments, including but not limited to providing