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United States Patent (10) Patent No.: US 7,323,169 B2 Goldenberg Et Al

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United States Patent (10) Patent No.: US 7,323,169 B2 Goldenberg Et Al USOO7323169B2 (12) United States Patent (10) Patent No.: US 7,323,169 B2 Goldenberg et al. (45) Date of Patent: Jan. 29, 2008 (54) SUSTAINED RELEASE FORMULATIONS 2005/0215470 A1* 9/2005 Ng et al. ...................... 514/12 (75) Inventors: Merrill S. Goldenberg, Thousand FOREIGN PATENT DOCUMENTS Oaks, CA (US); Jian Hua Gu, 3 SA 3. Thousand Oaks, CA (US) WO WO 94,08599 4f1994 WO WO 98,10649 3, 1998 (73) Assignee: Amgen Inc., Thousand Oaks, CA (US) WO WO 99,04764 A1 * 2, 1999 WO WOOO, 51643 9, 2000 (*) Notice: Subject to any disclaimer, the term of this WO WO O1/32.218 5, 2001 patent 1s listed Ojusted under 35 WO WO2004O12522 A 2, 2004 U.S.C. 154(b) by 40 days. OTHER PUBLICATIONS (21)21) AppAppl. No.: 11/114,4739 Hatano et al. Size exclusionn chromatographicgrap analysisy of polyphenol-serum albumin complexes. Phytochemistry. 2003, vol. (22) Filed: Apr. 25, 2005 63, pp. 817-823.* Naurato et al. Interaction of Tannin with Human Salivary Histatins. (65) Prior Publication Data Journal of Agricultural and Food Chemistry. May, 4, 1999, vol. 47. No. 6, pp. 2229-2234.* US 2005/0271722 A1 Dec. 8, 2005 M. Chasin, “Biodegradable Polymers for Controlled Drug Deliv ery J.O. Hollinger Editor, Biomedical Applications of Synthetic Related U.S. Application Data Biodegradable Polymers CRC, Boca Raton, Florida (1995) pp. 1-15. (60) Provisional application No. 60/565,247, filed on Apr. T. Hayashi. “Biodegradable Polympers for Biomedical Uses' Prog. 23, 2004. Polym. Sci. 19:4 (1994) pp. 663-700. Harjit Tamber et al., “Formulation Aspects of Biodegradable Poly (51) Int. Cl. meric Microspheres for Antigen Delivery' Advanced Drug Delivery A6 IK S/37 (2006.01) Reviews, 57:3 (2005) pp. 35i-376. A6 IK 38/02 (2006.01) Zhang, Y.-J. et al., “Association of Tannins and Related Polyphenols A6 IK 38/08 (2006.01) with Cyclic Peptide Gramicidin S.” Chem. Pharm. Bull., 50(2), pp. A6 IK 39/395 (2006.01) 258-262 (2002); published by Pharmaceutical Society of Japan. F2: f15: Matsuo, A. et al., “Interaction of Peptides Having a Turn Structure (52) U.S. Cl. ......................... 424/130.1: 514/2: 514/15; with Tannins.” Peptide Science 2001, pp. 205-206, H. Aoyagi (Ed.); 514f785 The Japanese Peptide Society (2002). (58) Field of Classification Search ..................... None Charlton, A. J. et al., “Polyphenol/Peptide Binding and Precipita See application file for complete search history. tion.” J. Agric. Food Chem. 50, pp. 1593-1601 (2002); published by American Chemical Society. (56) References Cited * cited by examiner U.S. PATENT DOCUMENTS Primary Examiner Jeffrey Edwin Russel 5,019,400 A 5, 1991 Gombotz et al. (74) Attorney, Agent, or Firm—Foley & Lardner LLP: 5, 192,741 A 3, 1993 Orsolini et al. Joseph P. Meara 5,916,597 A 6, 1999 Lee et al. 5,922,253 A 7, 1999 Herbert et al. (57) ABSTRACT 5.962.522. A 10, 1999 Wacher et al. 5981.474. A 11, 1999 Manila The present invention relates broadly to the field of sus 6,180,666 B1 1/2001 Wacher et al. tained release formulations. More specifically, the invention 6,428,818 B1 8, 2002 Morre et al. describes compositions and methods relating to formulating 6,531,154 B1 3/2003 Mathiowitz et al. proteins and/or peptides with purified gallic acid esters. In 6,613.358 B2 9/2003 Randolph et al. one example, the gallic acid ester is PentaGalloylGlucose 6,759,064 B2 7/2004 Morre et al. (PGG) and in anther example the gallic acid ester is epigal 2002/01 1994.6 A1* 8, 2002 Gen. ............................ 514,44 locatechin gallate (EGCG). 2002fO151582 A1 10, 2002 Dou et al. 2004/O142048 A1 7/2004 Morre et al. 25 Claims, No Drawings US 7,323,169 B2 1. 2 SUSTAINED RELEASE FORMULATIONS within an effective window for a time period sufficient to achieve the desired effect and to avoid excessive concen This Application claims the benefit of priority to U.S. trations, which may lead to side effects or untoward results. Provisional Application Ser. No. 60/565,247, filed Apr. 23, It is often difficult to achieve the desired release kinetics 2004. 5 with monolithic microparticles as the fraction of the active agent released within the first day after administration is FIELD OF THE INVENTION often dependent on the loading level of the drug. Yet another desirable characteristic of sustained delivery The present invention relates broadly to the field of technologies, particularly when applied to the delivery of Sustained release formulations. More specifically, the inven 10 macromolecules, is that the integrity of the active agent is tion describes compositions and methods relating to formu maintained during manufacture. This is often a difficult lating proteins and/or peptides with purified gallic acid challenge as most protein and peptide drugs are dependent esters. In one example, the gallic acid ester is PentaGalloyl on a three dimensional conformation for their bioactivity Glucose (PGG), where gallic acid is also known as 3,4, 5 and that conformation can easily be compromised. For trihydroxybenzoic acid and in another example the gallic 15 example, most of the polymers that are used to manufacture acid ester is epigallocatechin gallate (EGCG). controlled release parenteral preparations are not soluble in water and consequently the protein or peptide is exposed to BACKGROUND an organic solvent in the encapsulation step. Examples of other undesireable stresses that are associated with manu To achieve continuous delivery of the protein or peptide facturing of controlled release preparations that may com in Vivo, a Sustained release or Sustained delivery formulation promise the integrity of any particular active agent are high is desirable to avoid the need for repeated administrations. shear forces used to form droplets of the polymer solution in One approach for Sustained drug delivery is by microencap an continuous phase, exposure to polymerization reactions, Sulation, in which the active ingredient is enclosed within a high temperatures and undesirably low or high pH values. polymeric membrane to produce microparticles. 25 Another desirable attribute of sustained release modalities It has been shown that one can encapsulate a biologically is that the integrity of the active agent, particularly proteins active or pharmaceutically active agent within a biocompat or peptides, is retained within the microparticles during ible, biodegradable wall forming material Such as a polymer, release. Depending on the chosen duration of release, this to provide sustained or delayed release. In these methods the period can be from a few days up to several months. For agent or drug is typically dissolved, dispersed or emulsified, 30 conventional polymer matrix systems formed of PLGA the using stirrers, agitators, or other dynamic mixing techniques, acidic microenvironment formed during biodegradation of in one or more solvents containing the wall forming mate the polymer may degrade active agents incorporated therein rial. The solvent is then removed resulting in the formation during in vitro and in Vivo incubation. of microparticles encapsulating the agent or drug. These The prior art describes various sustained delivery com microparticles can then be administered to a patient. 35 positions and methods for making them, for example, U.S. The importance of biocompatible and/or biodegradable Pat. Nos. 5,916,597; 5,019,400; 5,922,253; and 6,531,154. polymers as carriers for parenteral drug delivery systems is The in vivo release of incorporated active agents from now well established. Biocompatible, biodegradable, and biocompatible and biodegradable polymers is, in many relatively inert substances such as poly(lactide) (PLA) or cases, initially high or low, and therefore non-uniform poly(lactide-co-glycolide) (PLGA) microspheres or films 40 throughout the life of the delivery device. Additionally, containing the active agent to be administered are commonly microencapsulation with polymers tends to provide long utilized sustained-release devices (for review, see M. Cha term Sustained delivery of peptides ranging from two weeks sin, Biodegradable polymers for controlled drug delivery. In: to nine months or longer whereas there is a need for shorter J. O. Hollinger Editor, Biomedical Applications of Synthetic term delivery profiles for certain medicaments. Thus, there Biodegradable Polymers CRC, Boca Raton, Fla. (1995), pp. 45 is a need in the art for Sustained release compositions with 1-15; T. Hayashi, Biodegradable polymers for biomedical release profiles of less than about a week or two. uses. Prog. Polym. Sci. 194 (1994), pp. 663-700; and Harjit Tamber, Pal Johansen, Hans P. Merkle and Bruno Gander, SUMMARY OF THE INVENTION Formulation aspects of biodegradable polymeric micro spheres for antigen delivery Advanced Drug Delivery 50 The present invention provides pharmaceutical composi Reviews, Volume 57, Issue 3, 10 Jan. 2005, Pages 357-376). tions comprising a stable Sustained release complex com However, there still exist many challenges to the design of posed of a protein and/or peptide and a gallic acid ester that delivery systems for active agents. A basic requirement for allow for sustained delivery of the protein or peptide in vivo Such delivery systems is that the materials used are accept upon administration of the complex. Accordingly, the com able for parenteral application. As mentioned above, it is 55 plex of the invention can permit continuous delivery of a desirable that the materials used are biodegradable for pharmaceutically active peptide to a subject for periods of formulations intended for repeated administration. Another time less than about one or two weeks. generally desirable quality is biocompatibility: the materials The complex of the invention is formed by combining a should be tolerated well and biodegradation should produce protein or peptide and a gallic acid ester under conditions innocuous compounds that are either eliminated from the 60 Such that a complex is formed.
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