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(12) United States Patent (10) Patent No.: US 6,565,889 B2 Zasadzinski Et Al

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(12) United States Patent (10) Patent No.: US 6,565,889 B2 Zasadzinski Et Al USOO6565889B2 (12) United States Patent (10) Patent No.: US 6,565,889 B2 Zasadzinski et al. 45) Date of Patent: MaV 20,9 2003 (54) BILAYER STRUCTURE WHICH (56) References Cited ENCAPSULATES MULTIPLE CONTAINMENT UNITS AND USES U.S. PATENT DOCUMENTS THEREOF 4,078,052 A 3/1978 Papahadjopoulos 5,004,566 A 4/1991 Schnur et al. .............. 260/403 (75) Inventors: Joseph A. Zasadzinski, Santa Barbara, 5,492,696 A 2/1996 Price et al. ................. 424/417 CA (US); Scott A. Walker, White Bear 5,618,560 A 4/1997 Bar-Shalom et al. ....... 424/486 Lake, MN (US); Michael T. Kennedy, 5,643,574 A 7/1997 Gould-Fogerite etal. 424/184.1 Oak Park, CA (US); Edward T. Kisak, 5,723,147 A 3/1998 Kim et al. Santa it's Bret A. 5,855,911. A * 1/1999 Lopez-Berestein et al. 424/450 Coldren, Santa Barbara, CA (US) 6,045,955 A 4/2000 Vincent (73) Assignee: The Regents of the University of OTHER PUBLICATIONS California, Oakland, CA (US) Allen, T. M., Current Opinion in Colloid and Interface * ) Notice: Sub disclai h f thi Science 1, 645–651 (1996) (Exhibit 32). (*) Otice: tE. EME Lasic, D. D. et al., Current Opinion in Solid State and U.S.C. 154(b) by 0 days. Materials Science, 1,392–400 (1996) (Exhibit 33). Whitesides,IleSideS, T.1. H.Fl. and RossKOSS J. ColloidCOttola and Interface SScience, 169, 48–59 (1995) (Exhibit 34). (21)21) Appl.ppl. No.:No 09/842,2401842, Zasadzinski, J. A., Current Opinion in Solid State and Materials Science 2, 345–349 (1997) (Exhibit 35). (22) Filed: Apr. 24, 2001 Chiruvolu, Shivkumar et al., “Higher Order Self-Assembly of Vesicles by Site-Specific Binding.” Science, (65) Prior Publication Data 264:1753–1756. Jun. 17, 1994. (Exhibit 6). Papahadjopoulos, D. et al., “Effects of Proteins on Thermo US 2002/0061331 A1 May 23, 2002 tropic Phase Transitions of Phospholipid Membranes,” Bio Related U.S. ApplicationO O Data chimica et Biophysica Acta, 401:317-335. 1975. (Exhibit 7). (List continued on next page.) (63) Continuation-in-part of application No. 09/139,045, filed on Aug. 24, 1998, now Pat. No. 6,221,401, which is a continu- Primary Examiner James M. Spear tips. Eig No. 08/980,332, filed on Nov. (74) Attorney, Agent, or Firm Mandel & Adriano (60) Provisional application No. 60/245,701, filed on Nov. 2, 2000, and provisional application No. 60/032,306, filed on (57) ABSTRACT Dec. 2, 1996. The present invention provides compositions and methods (51) Int. Cl. ............................ A61K 9/14; A61 K9/16; of preparing a bilayer Structure for encapsulating multiple A61K 9/50 containment units. These containment units can contain (52) U.S. Cl. ....................... 424/490; 424/423; 424/427; therapeutic, diagnostic agents or imaging agents that can be 424/430; 424/434; 424/435; 424/436; 424/444; released through the bilayer Structure. A Suitable example of 424/450; 424/451; 424/464; 424/449 Such a containment unit is a unilamellar or multilamellar (58) Field of Search ................................. 424/490, 423, Vesicle. 424/427, 430, 434, 435, 436, 444, 450, 489, 498 39 Claims, 13 Drawing Sheets s t LFC-BPFE WESCLES O. e O c) s Ois . t AC3REAES XRSTC: ti, 303-33 SSESL US 6,565,889 B2 Page 2 OTHER PUBLICATIONS Leckband, D. et al., BiophyS. J., 69, (1995), 1162–1169. Papahadjopoulos, D. et al., “Cochleate Lipid Cylinders: (Exhibit 19). Formation by Fusion of Unilamellar Lipid Vesicles,” Bio Leckband, D. et al., Nature, 376, (1995), 617-618. (Exhibit chimica et Biophysica Acta,394:483–491. 1975. (Exhibit 8). 20). Papahadjopoulos, D. et al., “Induction of Fusion in Pure Loughrey, H. C. et al., Biochim. Biophys. Acta, 1028, (1990), Phospholipid Membranes by Calcium Ions and Other Diva 73–81 (Exhibit 21). lent Metals,” Biochimica et Biophysica Acta, 448:265-283. Mayer, E. (1985) J. Microsc. 140, 3-15. (Exhibit 22). 1976. (Exhibit 9). Noppl-Simson, D.A. et al., Biophysical Journal, 70, (1996), Freireich, Emil J. et al., “Quantitative Comparison of Tox 1391–1401. (Exhibit 23). icity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey, and Man,” Cancer Chemotherapy Reports, Papahadjopoulos, D., et al., (1974) Biochim. Biophys. Acta, 50(4):219–244. May 04, 1966. (Exhibit 10). 401, 317–335. (Exhibit 24). Ahl, P. L., et al. Biochimica et Biophysica Acta 1195, (1994), Simon, S.A., and McIntosh, T.J. (1984) Biochim. BiophyS. 237-244. (Exhibit 11). Acta, 773, 169–172. (Exhibit 25). Allen, T. M. et al., Advanced Drug Delivery Reviews, 16, Walker, S.A. et al., Nature, 387, (1997), 61–64. (Exhibit 26). (1995), 267–284. (Exhibit 12). Zasadzinski, J.A. i et al., J. Electron Microsc. Technique, 13, Boni, L.T. et al., Biochim. Biophys. Acta, 1146, (1993), (1989), 309-334. Exhibit 27). 247–257. (Exhibit 13). Cullis, P.R. et al., Biochim. Biophys. Acta, 1997, 1331, Zasadzinski, J.A. et al., Current Opinion in Colloid and 187-211. (Exhibit 14). Interface Science, 2001, 6, 89–90. (Exhibit 28). Emans, N. et al., Biophysical Journal, 69, (1995), 716-728. Kisak, E., et al. Langmuir 16, 2825-2831. (2000) (Exhibit (Exhibit 15). 29). Jung, H.T. et al., Proc. Natl. Acad. Sci. USA, 2001, 98, Spector, M. S., J. A. Zasadzinski, M. B. Sankaram, Lang 1353–1357. (Exhibit 16). muir 12, 4704–4708. (1996) (Exhibit 30). Kim, T., S. Murdande, A. Gruber, S. Kim, Anesthesiology Walker, S. A. et al., Langmuir, 13, 5076–5081. (1997) 85, (1996), 331-338. (Exhibit 17). (Exhibit 31). Leckband, D. E. et al., Biochemistry,33, (1994),4611-4624. (Exhibit 18). * cited by examiner U.S. Patent May 20, 2003 Sheet 1 of 13 US 6,565,889 B2 U.S. Patent May 20, 2003 Sheet 2 of 13 US 6,565,889 B2 U.S. Patent May 20, 2003 Sheet 3 of 13 US 6,565,889 B2 DOPS-BDPPE. VESICLES DLPC-BDPPE VESICLES COCHLEATED CYLINDERS Add LARGE WESICLE AGGREGATES H - EXTRUSION STREPAVIDIN C ACTIVATED CYLINDERS SIZED ACTIVATED AGGREGATES CYLINDER-AGGREGATE ASSEMBLY | FIG. 5 VESOSOME U.S. Patent May 20, 2003 Sheet 4 of 13 US 6,565,889 B2 FIG. 4 EXAMPLE 1 PROCESS EXAMPLE 2 PROCESS BIOTIN-LABELLED VESICLES BIOTIN-LABELLED VESICLES 9 C3 9 C3 SP 9 o', 9 p. Add STREPTAVIDIN STREPTAVIDIN AT is: 3. CONTROLLED RATIOS LARGE WESICLE AGGREGATES EXTRUSION THROUGH FILTERS SELF-LIMITED AGGREGATES PURIFICATION, REMOVAL OF DEBRIS U.S. Patent May 20, 2003 Sheet 5 of 13 US 6,565,889 B2 U.S. Patent May 20, 2003 Sheet 6 of 13 US 6,565,889 B2 FIG. 6 AGGREGATION VARYING LIGAND TO RECEPTOR RATIOS A B-X:S (BIOTIN-X/STREPTAVIDIN RATIO) U.S. Patent May 20, 2003 Sheet 7 of 13 US 6,565,889 B2 U.S. Patent May 20, 2003 Sheet 8 of 13 US 6,565,889 B2 res U.S. Patent May 20, 2003 Sheet 9 of 13 US 6,565,889 B2 % i tre U.S. Patent May 20, 2003 Sheet 10 Of 13 US 6,565,889 B2 i gure ( U.S. Patent May 20, 2003 Sheet 11 of 13 US 6,565,889 B2 Figure 11 U.S. Patent May 20, 2003 Sheet 12 of 13 US 6,565,889 B2 gure U.S. Patent May 20, 2003 Sheet 13 of 13 US 6,565,889 B2 Fig 3. US 6,565,889 B2 1 2 BILAYER STRUCTURE WHICH (MVL)) J. A. Zasadzinski, Current Opinion in Solid State ENCAPSULATES MULTIPLE and Materials Science 2, 345 (1997); M. S. Spector, J. A. CONTAINMENT UNITS AND USES Zasadzinski, M. B. Sankaram, Langmuir 12, 4704 (1996); T. THEREOF Kim, S. Murdande, A. Gruber, S. Kim, Anesthesiology 85, 331 (1996). Depofoam TM is a multivesicular particle that is This application claims the priority of provisional created by multiple emulsification Steps. A defined lipid composition is dissolved in a volatile Solvent. The dispersed application, U.S. Serial No. 60/245,701, filed Nov. 2, 2000 lipids in the Solvent are vigorously mixed with water to form and is a continuation-in-part application of U.S. Ser. No. a first emulsion, designated a Solvent continuous emulsion. 09/139,045, filed Aug. 24, 1998, U.S. Pat. No. 6,221,401 This first emulsion is then added to a second water/solvent which is a continuation-in-part application of U.S. Ser. No. emulsion and emulsified to form a water in Solvent in water 08/980,332, filed Nov. 28, 1997, now abandoned which double emulsion. The solvent is removed from the mixture, claims the priority of provisional application, U.S. Serial resulting in discrete, foam-like Spherical Structures consist No. 60/032,306, filed Dec. 2, 1996, all of which are incor ing of bilayer-separated water compartments. The minimum porated herein, in their entirety, by reference. size of these structures is about 5 to 10 microns. Depo This invention was made with Government support 15 foam TM particles do not include a distinct bilayer structure under NSF grant DMR-9123048 and NIH grant GM47334. that encapsulates the multivesicular particles, i.e. there are The Government has certain rights in this invention. no individual, distinct interior vesicles. Therefore, the inte Throughout this application various publications are ref rior compartment must share the bilayer walls. Because of erenced. The disclosures of these publications in their entire the emulsification in solvents, these Depofoam TM particles ties are hereby incorporated by reference into this are not capable of encapsulating existing vesicles, or Sensi application, in order to more fully describe the State of the tive biological materials, that degrade or denature in the art to which this invention pertains.
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