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(12) United States Patent (10) Patent No.: US 7,732,399 B2 Goldenberg Et Al

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(12) United States Patent (10) Patent No.: US 7,732,399 B2 Goldenberg Et Al US007732399B2 (12) United States Patent (10) Patent No.: US 7,732,399 B2 Goldenberg et al. (45) Date of Patent: *Jun. 8, 2010 (54) SUSTAINED RELEASE FORMULATIONS 2002fO151582 A1 10, 2002 Dou et al. 2003/O190307 A1* 10, 2003 DiBiase et al. ............. 424,856 (75) Inventors: Merrill S. Goldenberg, Thousand Oaks, 2004/0142048 A1 7/2004 Moore et al. CA (US); Jian Hua Gu, Thousand Oaks 2005/0180925 A1* 8/2005 Chaudry ...................... 424/46 CA (US s s 2005/0215470 A1 9/2005 Ng et al. FOREIGN PATENT DOCUMENTS (73) Assignee: Amgen Inc., Thousand Oaks, CA (US) GB 92.9405 A 6, 1963 (*) Notice: Subject to any disclaimer, the term of this GB 1234.805. A 6, 1971 patent is extended or adjusted under 35 W W 3. t E. U.S.C. 154(b) by 193 days. WO WO99,04764 2, 1999 This patent is Subject to a terminal dis- W W 995, 239, claimer. WO WO 2004/O12522 2, 2004 (21) Appl. No.: 11/847,984 OTHER PUBLICATIONS 1-1. Yan et al. Identification of histatins as tannin-binding proteins in (22) Filed: Aug. 30, 2007 human saliva. Biochemical Journal. 1995, vol. 311, pp. 341-347.* O O Charlton, A. J. et al., “Polyphenol/Peptide Binding and Precipita (65) Prior Publication Data tion.” J. Agric. Food Chem. 50, pp. 1593-1601 (2002); published by US 2007/0292506 A1 Dec. 20, 2007 Chasin,American M.. Chemical “Biodegradable Society. Polymers for Controlled Drug Deliv O O ery,” J.O. Hollinger Editor, Biomedical Applications of Synthetic Related U.S. Application Data Biodegradable Polymers CRC, Boca Raton, FL (1995), pp. 1-15. (63) Continuation of application No. 1 1/114,473, filed on Hatano, et al., “Size Exclusion Chromatographic Analysis of Apr. 25, 2005, now Pat. No. 7,323,169. Polyphenol-Serum Albumin Complexes.” Phytochemistry, 2003, vol. 63, pp. 817-823. (60) Provisional application No. 60/565,247, filed on Apr. Hyashi, T. "Biodegradable Polymers for Biomedical Uses.” Prog. 23, 2004. Polym. Sci 19:4 (1994), pp. 663-700. Matsuo, A. et al., “Interaction of Peptides Having a Turn Structure (51) Int. Cl. with Tannins.” Peptide Science 2001, pp. 205-206, H. Aoyagi (Ed.); A6 IK 38/02 (2006.01) The Japanese Peptide Society (2002). A6 IK 38/03 (2006.01) Naurato, et al., “Interaction of Tannin with Human Salivary Histatins,” Journal of Agricultural and Food Chemistry, May 4, 1999, A6 IK 38/08 (2006.01) vol. 47, No. 6, pp. 2229-2234. A6 IK 47/4 (2006.01) Tamber, H. et al., “Formulation Aspects of Biodegradable Polymeric (52) U.S. Cl. .............................. 514/2; 514/15: 514/785 Microspheres for Antigen Delivery.” Advanced Drug Delivery (58) Field of Classification Search ....................... None Reviews, 57:3 (2005) pp. 351-376. See application file for complete search history. Zhang, Y.-J. et al., “Association of Tannins and Related Polyphenols with the Cyclic Peptide Gramicidin S.” Chem. Pharm. Bull., 50(2), (56) References Cited pp. 258-262 (2002); published by Pharmaceutical Society of Japan. U.S. PATENT DOCUMENTS * cited by examiner 2.849,370 A * 8, 1958 Petersen et al. ................ 514.f4 Primary Examiner Jeffrey E. Russel 5,019,400 A 5, 1991 Gombotz et al. (74) Attorney, Agent, or Firm Nisan A. Steinberg 5,151.265 A * 9/1992 Hwang-Felgner et al. .. 424/85.5 5, 192,741 A 3, 1993 Orsolini et al. (57) ABSTRACT 5,916,597 A 6, 1999 Lee et al. 5,922,253 A 7, 1999 Herbert et al. The present invention relates broadly to the field of sustained 5,962.522 A 10, 1999 Wacher et al. 5,981,474 A 11/1999 Manning et al. release formulations. More specifically, the invention 6,180,666 B1 1/2001 Wacher et al. describes compositions and methods relating to formulating 6,428,818 B1 8, 2002 Morre et al. proteins and/or peptides with purified gallic acid esters. In 6,531,154 B1 3/2003 Mathiowitz et al. one example, the gallic acid ester is PentaGalloylGlucose 6,613.358 B2 9/2003 Randolph et al. (PGG) and in anther example the gallic acid ester is epigal 6,759,064 B2 7/2004 Morre et al. locatechin gallate (EGCG). 7.323,169 B2 * 1/2008 Goldenberg et al. ..... 424,130.1 2002/01 1994.6 A1 8, 2002 Gen 21 Claims, No Drawings US 7,732,399 B2 1. 2 SUSTAINED RELEASE FORMULATIONS Another desirable attribute is sufficiently good control of the release of the encapsulated active agent. It is generally This application is a continuation of U.S. patent applica important to maintain the concentration of the active agent tion Ser. No. 1 1/114,473, filed Apr. 25, 2005, which issued as within an effective window for a time period sufficient to U.S. Pat. No. 7,323,169 on Jan. 29, 2008, which in turn claims achieve the desired effect and to avoid excessive concentra priority to Provisional Application Ser. No. 60/565,247, filed tions, which may lead to side effects or untoward results. It is Apr. 23, 2004, the entire contents of which are incorporated often difficult to achieve the desired release kinetics with by reference herein. monolithic microparticles as the fraction of the active agent released within the first day after administration is often FIELD OF THE INVENTION 10 dependent on the loading level of the drug. Yet another desirable characteristic of sustained delivery The present invention relates broadly to the field of sus technologies, particularly when applied to the delivery of tained release formulations. More specifically, the invention macromolecules, is that the integrity of the active agent is describes compositions and methods relating to formulating maintained during manufacture. This is often a difficult chal proteins and/or peptides with purified gallic acid esters. In 15 lenge as most protein and peptide drugs are dependent on a one example, the gallic acid ester is PentaGalloylGlucose three dimensional conformation for their bioactivity and that (PGG), where gallic acid is also known as 3.4.5 trihydroxy conformation can easily be compromised. For example, most benzoic acid and in another example the gallic acid ester is of the polymers that are used to manufacture controlled epigallocatechin gallate (EGCG). release parenteral preparations are not soluble in water and consequently the protein or peptide is exposed to an organic BACKGROUND Solvent in the encapsulation step. Examples of other undesir able stresses that are associated with manufacturing of con trolled release preparations that may compromise the integ To achieve continuous delivery of the protein or peptide in rity of any particular active agent are high shear forces used to Vivo, a Sustained release or Sustained delivery formulation is 25 form droplets of the polymer Solution in an continuous phase, desirable to avoid the need for repeated administrations. One exposure to polymerization reactions, high temperatures and approach for Sustained drug delivery is by microencapsula undesirably low or high pH values. tion, in which the active ingredient is enclosed within a poly Another desirable attribute of sustained release modalities meric membrane to produce microparticles. is that the integrity of the active agent, particularly proteins or It has been shown that one can encapsulate a biologically 30 peptides, is retained within the microparticles during release. active or pharmaceutically active agent within a biocompat Depending on the chosen duration of release, this period can ible, biodegradable wall forming material such as a polymer, be from a few days up to several months. For conventional to provide sustained or delayed release. In these methods the polymer matrix systems formed of PLGA the acidic microen agent or drug is typically dissolved, dispersed or emulsified, Vironment formed during biodegradation of the polymer may using stirrers, agitators, or other dynamic mixing techniques, 35 degrade active agents incorporated therein during in vitro and in one or more solvents containing the wall forming material. in vivo incubation. The solvent is then removed resulting in the formation of The prior art describes various sustained delivery compo microparticles encapsulating the agent or drug. These micro sitions and methods for making them, for example, U.S. Pat. particles can then be administered to a patient. Nos. 5,916,597; 5,019,400; 5,922,253; and 6,531,154. The in The importance of biocompatible and/or biodegradable 40 Vivo release of incorporated active agents from biocompat polymers as carriers for parenteral drug delivery systems is ible and biodegradable polymers is, in many cases, initially now well established. Biocompatible, biodegradable, and high or low, and therefore non-uniform throughout the life of relatively inert substances such as poly(lactide) (PLA) or the delivery device. Additionally, microencapsulation with poly(lactide-co-glycolide) (PLGA) microspheres or films polymers tends to provide long term Sustained delivery of containing the active agent to be administered are commonly 45 peptides ranging from two weeks to nine months or longer utilized sustained-release devices (for review, see M. Chasin, whereas there is a need for shorter term delivery profiles for Biodegradable polymers for controlled drug delivery. In: J.O. certain medicaments. Thus, there is a need in the art for Hollinger Editor, Biomedical Applications of Synthetic Bio Sustained release compositions with release profiles of less degradable Polymers CRC, Boca Raton, Fla. (1995), pp. than about a week or two. 1-15; T. Hayashi, Biodegradable polymers for biomedical 50 uses. Prog. Polym. Sci. 194 (1994), pp. 663-700; and Harjit SUMMARY OF THE INVENTION Tamber, Pal Johansen, Hans P. Merkle and Bruno Gander, Formulation aspects of biodegradable polymeric micro The present invention provides pharmaceutical composi spheres for antigen delivery Advanced Drug Delivery tions comprising a stable Sustained release complex com Reviews, Volume 57, Issue 3, 10 Jan.
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