US 2013 0116341A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0116341 A1 Askari et al. (43) Pub. Date: May 9, 2013 (54) N-VVO GELLING PHARMACEUTICAL filed on Aug. 31, 2010, provisional application No. PRE-FORMULATION 61/332,197, filed on May 7, 2010. (75) Inventors: Syed H. Askari, San Jose, CA (US); Publication Classification George Horng, Millbrae, CA (US) (51) Int. Cl. (73) Assignee: MEDICUS BIOSCIENCES, LLC, San A647/34 (2006.01) Francisco, CA (US) (52) U.S. Cl. CPC ...................................... A61K47/34 (2013.01) (21) Appl. No.: 13/696,032 USPC ........................................ 514/772.3; 524/879 (22) PCT Fled: May 6, 2011 (57) ABSTRACT (86) PCT NO.: PCT/US11A35643 Provided herein are in vivo gelling pharmaceutical pre-for mulations forming biocompatible hydrogel polymers that are S371 (c)(1), polymerized in Vivo and kits comprising at least one nucleo (2), (4) Date: Jan. 15, 2013 philic compound or monomer unit, at least one electrophilic compound or monomer unit, and optionally at least one thera Related U.S. Application Data peutic agent. The biocompatible hydrogel polymer is bioab (60) Provisional application No. 61/387.841, filed on Sep. Sorbable and releases the therapeutic agent at a target site, 29, 2010, provisional application No. 61/378,730, avoiding systemic exposure. Patent Application Publication May 9, 2013 Sheet 1 of 2 US 2013/011 6341 A1 FIGURE 1 W Comparing DDP and DCP Elution - EF-daily SSS - - - - - - -& & CP-Eily iš. Š........................&. 3.s :S SS S. S. S S aSNCP-2x 3ily \sŠs ws S. ass s t S Y Yo Y V V v YY S v Y&\ssic Yxas &s SS ^ws assass & & Sas SSssssssssssssss $WasaSSS Xwas Patent Application Publication May 9, 2013 Sheet 2 of 2 US 2013/011 6341 A1 FIGURE 2 xyYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY: Comparing Cumulative Elution with Time 90 c.c. SS &S US 2013/011 6341 A1 May 9, 2013 N-VVO GELLING PHARMACEUTICAL pound is a glycol, trimethylolpropane, pentaerythritol, hexa PRE-FORMULATION glycerol, or tripentaerythritol derivative. In preferred embodiments, the first compound is a pentaerythritol or hexa CROSS-REFERENCE glycerol derivative. In certain embodiments, the first com pound further comprises one or more polyethylene glycol 0001. This application claims the benefit of U.S. Provi sections. In some embodiments, the first compound is sional Application No. 61/387,841, filed Sep. 29, 2010, U.S. selected from the group consisting of ethoxylated pentaeryth Provisional Application No. 61/378,730, filed Aug. 31, 2010, ritol ethylamine ether, ethoxylated pentaerythritol propy and U.S. Provisional Application No. 61/332,197, filed May lamine ether, ethoxylated pentaerythritol amino acetate, 7, 2010, each of which are incorporated herein by reference in ethoxylated hexaglycerol ethylamine ether, ethoxylated their entirety. hexaglycerol propylamine ether, and ethoxylated hexaglyc erol amino acetate. In certain embodiments, the first com BACKGROUND OF THE INVENTION pound is selected from the group consisting of trimethylol 0002 Every year millions of people undergo systemic propane trimercaptoacetate, trimethylolpropane tri-3- treatments, such as chemotherapy for cancers, inflammatory mercaptopropionate, pentaerythritol tetramercaptoacetate, diseases, and chronic conditions. Systemic treatments, in pentaerythritol tetra-3-mercaptopropionate, ethoxylated tri which medications are injected or absorbed into the blood methylolpropane trimercaptoacetate, ethoxylated trimethy stream an circulated throughout the body, are currently the lolpropane tri-3-mercaptopropionate, ethoxylated pen only viable option to reach the site of these diseases even taerythritol tetramercaptoacetate, and ethoxylated though in most cases the disease is localized in a specific trimethylolpropane tri-3-mercaptopropionate. In some organ. However, the systemic approach produces toxic side embodiments, the molecular weight of the first compound is effects, such as profound nausea and vomiting, immunosup between about 1000 and 20000. pression and risk or life threatening infections, anemia, hair 0006. In certain embodiments, the electrophilic group is loss, kidney toxicity, and nerve damage. For many cancer an epoxide, N-Succinimidyl Succinate, N-Succinimidylglut patients the toxicity potential is so severe that chemotherapy arate, N-Succinimidyl Succinamide or N-Succinimidylglut cannot be given. In some instances, patients die of the side aramide. In some embodiments, the second compound is a effects rather than from the cancer. trimethylolpropane, glycerol, diglycerol, pentaerythritol, Sorbitol, hexaglycerol, tripentaerythritol, or polyglycerol SUMMARY OF THE INVENTION derivative. In preferred embodiments, the second compound 0003 Provided herein are in vivo gelling pharmaceutical is a trimethylolpropane, pentaerythritol, or hexaglycerol pre-formulations, biocompatible hydrogel polymers, in vivo derivative. In some embodiments, the second compound fur polymerized biocompatible hydrogel polymers, and kits for ther comprises one or more polyethylene glycol sections. In preparing in vivo gelling pharmaceutical pre-formulations, certain embodiments, the second compound is selected from biocompatible hydrogel polymers, and in vivo polymerized the group consisting of ethoxylated pentaerythritol Succinim biocompatible hydrogel polymers. The pre-formulations and idyl Succinate, ethoxylated pentaerythritol Succinimidylglu hydrogel polymers comprise a mixture of compounds that tarate, ethoxylated pentaerythritol Succinimidylglutaramide, safely undergo polymerization to form a biocompatible ethoxylated hexaglycerol Succinimidyl Succinate, ethoxy hydrogel polymer at a target site. Using a minimally invasive lated hexaglycerol Succinimidyl glutarate, and ethoxylated delivery system (e.g., endoscopic or image guided), the poly hexaglycerol Succinimidyl glutaramide. In some embodi meric hydrogel formulation is delivered to the target site, ments, the second compound is selected from the group con where the pre-formulation solidifies into a biocompatible sisting of Sorbitol polyglycidyl ether, polyglycerol polygly hydrogel polymerata predetermined time to remain at the site cidyl ether, diglycerol polyglycidyl ether, glycerol of delivery. In some embodiments, the biocompatible hydro polyglycidyl ether, and trimethylolpropane polyglycidyl gel polymer comprises one or more therapeutic agents that ether. In certain embodiments, the molecular weight of the are released over time from the hydrogel polymer at the target second compound is between about 1000 and 20000. site, limiting exposure of healthy cells to the therapeutic 0007. In some embodiments, the therapeutic agent is inde agent. In certain embodiments, the biocompatible hydrogel pendently selected from the group consisting of an anticancer polymer degrades over time and is bioabsorbed. agent, an antiviral agent, an antibacterial agent, antifungal 0004. In one aspect provided herein is an in vivo gelling agent, an immunosuppressant agent, an hemostasis agent, pharmaceutical pre-formulation, comprising (a) at least one and an anti-inflammatory agent. water soluble first compound comprising more than one 0008. In certain embodiments, the gelling time of the bio nucleophilic group, (b) at least one water soluble second compatible hydrogel polymer is controlled by the pH of the compound comprising more than one electrophilic group, (c) aqueous buffer. In some embodiments, the gelling time is an aqueous buffer in the pH range of 5.0 to 9.0; and (d) between about 20 seconds and 5 minutes. In certain embodi optionally, one or more therapeutic agents; wherein mixing ments, the pH of the aqueous buffer is from about 6.9 to about the first compound, the second compound, and the optional 7.9. In some embodiments, the pH of the aqueous buffer is therapeutic agent in the aqueous buffer and delivering the about 7.4. In certain embodiments, the biocompatible hydro mixture to a target site in the human body generates the in gel polymer gels at a predetermined time. In some embodi Vivo gelling pharmaceutical pre-formulation Such that the in ments, the biocompatible hydrogel polymer is a bioabsorb Vivo gelling pharmaceutical pre-formulation at least in part able polymer. In certain embodiments, the biocompatible polymerizes and gels at the target site to form a biocompatible hydrogel polymer is bioabsorbed within about 1 to 70 days. In hydrogel polymer. Some embodiments, the biocompatible hydrogel polymer is 0005. In some embodiments, the nucleophilic group is a substantially non-bioabsorbable. In certain embodiments, the thiol or amino group. In certain embodiments, the first com in vivo gelling pharmaceutical pre-formulation further com US 2013/011 6341 A1 May 9, 2013 prises a radiopaque material or a pharmaceutically acceptable ethoxylated hexaglycerol propylamine ether, ethoxylated tri dye. In certain embodiments, the radiopaque material is methylolpropane tri-3-mercaptopropionate, ethoxylated selected from Sodium iodide, potassium iodide, barium Sul hexaglycerolamino acetate. fate, tantalum, VISIPAQUE(R), OMNIPAQUER, or 0012. In some embodiments, the electrophilic group is an HYPAQUE(R), or combinations thereof. epoxide, N-Succinimidyl Succinate, N-Succinimidyl glut arate, N-Succinimidyl Succinamide, or N-Succinimidylglut 0009. In some embodiments, the therapeutic