Controlled Release Hydrogels

Abstract

Formulations and methods for their preparation including a hydrogel including a crosslinked matrix comprising a polymer, and a one or more liposomes containing a therapeutic agent.

1 . A controlled release hydrogel composition for administration of a therapeutic agent to a mammal, comprising a cross-linked polymer matrix, and at least one liposome physically entrapped within said polymer matrix, said at least one liposome having at least one therapeutically active agent contained therein, said hydrogel composition providing a controlled release of said therapeutically active agent when the composition is administered to a bodily compartment of said mammal. 
   
   
       2 . The composition of  claim 1 , wherein said polymer comprises at least two functional or reactive groups selected from the group consisting of amino, carboxyl, thiol, hydroxyl, and any combination thereof. 
   
   
       3 . The composition of  claim 1 , wherein said polymer is a poly (alkylene oxide) derivative. 
   
   
       4 . The composition of  claim 3 , wherein said polymer is prepared from a ω-diamino-poly (ethylene glycol) and thiomalic acid; a co-dihydroxy-poly (ethylene glycol) and thiomalic acid; or a ω-dicarboxy-PEG-subunits and lysine, wherein free carboxy groups on said lysine are derivatized to provide thiol groups. 
   
   
       5 . The composition of  claim 4 , wherein said thiol groups on said polymer are cross-linked by thioether or disulfide bonds. 
   
   
       6 . The composition of  claim 1  wherein said matrix has at least one controlled release in-vivo kinetic profile selected from the group consisting of zero order, pseudo zero order, and first order. 
   
   
       7 . The composition of  claim 1  which provides a constant rate of release of said therapeutically active agent when said pharmaceutical composition is administered to a mammal. 
   
   
       8 . The composition of  claim 1 , wherein said cross-linked polymer is a polyalkylene oxide chemically modified to include thiol groups, reacted with a vinylsulfone cross-linking agent to form said matrix. 
   
   
       9 . The composition of  claim 1 , wherein said cross-linked polymer is a diamino polyethyleneglycol crosslinked with a cross-linking agent selected from the group consisting of a bifunctional disulfide-forming cross-linking agent, a bifunctional thioether-forming cross-linking agent, and combinations thereof. 
   
   
       10 . The composition of  claim 1 , wherein said therapeutically active agent is an antitumor agent, and the composition is deliverable in proximity to a tumor. 
   
   
       11 . The composition of  claim 1 , wherein said therapeutic agent diffuses at a controlled rate from said hydrogel composition in situ into said body compartment. 
   
   
       12 . The composition of  claim 1 , wherein said at least one liposome is a plurality of liposomes. 
   
   
       13 . The composition of  claim 12 , wherein each of said plurality of liposomes encapsulates said therapeutic agent. 
   
   
       14 . The composition of  claim 1 , wherein said therapeutic active agent is loaded into said at least one liposome through an active loading process. 
   
   
       15 . The composition of  claim 1 , wherein said at least one liposome comprises a material selected from the group consisting of a phosphatidic acid, a phosphatidyl choline with both saturated and unsaturated lipids, a phosphatidyl ethanolamine, a phosphatidylglycerol, a phosphatidylserines, a phosphatidylinositols, a lysophosphatidyl derivatives, a cardiolipin, a acyl-y-alkyl phospholipids, and combinations thereof. 
   
   
       16 . The composition of  claim 1 , wherein said at least one therapeutic agent is and anti-tumor agent. 
   
   
       17 . The composition of  claim 16 , wherein said anti-tumor agent is a camptothecin, a pharmaceutically acceptable salt thereof, or analog thereof. 
   
   
       18 . The composition of  claim 16 , wherein said anti-tumor agent is selected from the group consisting of camptothecin, topotecan, irinotecan, a homocaptothecin, a homosilatecan, and pharmaceutically acceptable salts thereof. 
   
   
       19 . The composition of  claim 18 , which is suitable for the treatment of tumors associated with cancers of the esophagus, the stomach, the intestines, the rectum, the oral cavity, the pharynx, the larynx, the lung, the colon, the breast, the cervix uteri, the corpus endometrium, the ovaries, the prostate, the testicles, the bladder, the kidneys, the liver, the pancreas, the bone, the connective tissues, the skin, the eyes, the brain and the central nervous system, as well as cancer of the thyroid, leukemia, Hodgkin's disease, lymphomas other than those related to Hodgkin, multiple myelomas and combinations thereof. 
   
   
       20 . The composition of  claim 19 , which is suitable for subcutaneous administration. 
   
   
       21 - 25 . (canceled)