In situ controlled release drug delivery system

Abstract

A system is described for long-term controlled release delivery of a drug or a therapeutic agent. According to the invention, one or more drugs or therapeutic agents contained in microspheres are mixed with a temperature sensitive hydrogel which is then introduced directly to the desired situs of the drug or therapeutic agent. The temperature sensitive hydrogel may also contain a drug or a therapeutic agent, for example, a pain relieving drug, for a short-term controlled release. The temperature sensitive hydrogel is in liquid state at room temperature, but upon injection, shortly becomes gelatinous. This system is particularly suitable for treatment of diseases, disorders, or conditions, for example, tumors, discogenic back pain, or arthritis, warranting localized administration of a drug or a therapeutic agent. In addition, the specification provides a method for production of a drug- or therapeutic agent-containing microspheres.

1 . A method of introducing a drug or therapeutic agent to a specific site within an animal comprising:
 introducing to a specific site in an animal a hydrogel mixture comprising: a plurality of drug or therapeutic agent and hydrogel, wherein said hydrogel is in liquid state at or about room temperature and a solid or gelatinous state at or about body temperature, wherein the drug or therapeutic agent is released at said site.   
     
     
         2 . The method of  claim 1  wherein said step of introducing is by injection. 
     
     
         3 . The method of  claim 1  wherein the hydrogel contains at least one drug or therapeutic agent to provide a short-term therapeutic effect. 
     
     
         4 . The method of  claim 1  wherein the hydrogel mixture comprises a drug or therapeutic agent from about 0.1% to about 70% of the hydrogel mixture. 
     
     
         5 . The method of  claim 1 , wherein the hydrogel comprises polymers selected from the group consisting of: N-isopropyl acrylamide polymer, ethylhydroxyethylcellulose, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide), poloxamers, PLURONICS® polymers, poly(ethylene glycol)/poly(D,L-lactic acid-co-glycolic acid) block co-polymers, polysaccharides, alginate, polyphosphazines, polyacrylates, TETRONICS™ polymers, polyethylene oxide-polypropylene glycol block copolymers and derivatives and analogs thereof. 
     
     
         6 . The method of  claim 1  wherein the drug or therapeutic agent contained in the hydrogel mixture is released in a controlled manner for a therapeutic effect. 
     
     
         7 . The method of  claim 1  wherein the drug or therapeutic agent is a local anesthetic selected from the group consisting of: amethocaine, articaine, benzocaine, bupivacaine, chloroprocaine, dibucaine, dyclonine, etidocaine, levobupivacaine, lidocaine, mepivacaine, oxethazaine, pramoxine, prilocaine, procaine, proparacaine, and ropivacaine. 
     
     
         8 . The method of  claim 1  wherein the drug or therapeutic agent is a narcotic analgesic selected from the group consisting of: alfentanil, alphaprodine, buprenorphine, butorphanol, codeine, codeine phosphate, cyclazocine, dextomoramide, dezocine, diamorphine, dihydrocodeine, dipianone, fedotozine, fentanyl, hydrocodone, hydromorphone, ketobemidone, levorphanol, meptazinol, methadone, methadyl acetate, morphine, nalbuphine, norpropoxyphene, noscapine, oxycodone, oxymorphone, paregoric, pentazocine, pethidine, phenazocine, piritramide, propoxyphene, remifentanil, sufentanil, tilidine, and tramadol. 
     
     
         9 . The method of  claim 1  wherein the drug or therapeutic agent is a nonnarcotic analgesic selected from the group consisting of: aminosalicylic sodium, balsalazide, choline salicylate, mesalazine, olsalazine, para-amino salicylic acid, salicylic acid, salicylsalicylic acid, and sulphasalazine, ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and naproxen. 
     
     
         10 . The method of  claim 1 , wherein the drug or therapeutic agent is delivered to a site of musculoskeletal joint pain in an animal, wherein said drug or therapeutic agent is released at said site thereby providing pain relief. 
     
     
         11 . The method of  claim 10  wherein at least one site of musculoskeletal joint pain comprises an interverterbral disc, a hip, a knee, an ankle, a shoulder, a wrist or a finger. 
     
     
         12 . The method of  claim 1  wherein a chemotherapeutic drug or agent is delivered to a site of a tumor in an animal, wherein said drug or agent is released at said site thereby causing tumor regression. 
     
     
         13 . The method of  claim 12 , wherein said chemotherapeutic drug or agent is selected from the group consisting of: alkylating agents, antimetabolites, antibiotics, natural or plant derived products, hormones and steroids and platinum drugs. 
     
     
         14 . A method of treating back pain through controlled drug release comprising:
 injecting a pharmaceutical composition percutaneously into at least one interverterbral discs, said pharmaceutical composition comprising:   a temperature-sensitive hydrogel, wherein the hydrogel is in liquid state at or about room temperature and a solid or gelatinous state at or about body temperature; and   at least one pain relieving drug forming a hydrogel-drug mixture.   
     
     
         15 . The method of  claim 14  wherein the hydrogel-drug mixture comprises a drug or therapeutic agent from about 0.1% to about 70% of the hydrogel-drug mixture. 
     
     
         16 . A pharmaceutical composition for the delivery of a drug or therapeutic agent, comprising:
 a temperature-sensitive hydrogel, wherein the hydrogel is in liquid state at or about room temperature and a solid or gelatinous state at or about body temperature; and   at least one drug or therapeutic agent, wherein the drug or therapeutic agent is comprised in the hydrogel, thereby forming a hydrogel mixture that releases said drug or therapeutic agent.   
     
     
         17 . The composition of  claim 16  wherein the hydrogel comprises at least one drug or therapeutic agent to provide a short-term therapeutic effect. 
     
     
         18 . The composition of  claim 16  wherein the hydrogel mixture comprises a drug or therapeutic agent from about 0.1% to about 70% of the hydrogel mixture. 
     
     
         19 . The composition of  claim 16  wherein the hydrogel comprises polymers selected from the group consisting of: N-isopropyl acrylamide polymer, ethylhydroxyethylcellulose, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide), poloxamers, PLURONICS® polymers, poly(ethylene glycol)/poly(D,L-lactic acid-co-glycolic acid) block co-polymers, polysaccharides, alginate, polyphosphazines, polyacrylates, TETRONICS™ polymers, polyethylene oxide-polypropylene glycol block copolymers and derivatives and analogs thereof. 
     
     
         20 . The composition of  claim 16  wherein the at least one drug or therapeutic agent contained in the hydrogel mixture is released in a controlled manner and is (a) a local anesthetic selected from the group consisting of: amethocaine, articaine, benzocaine, bupivacaine, chloroprocaine, dibucaine, dyclonine, etidocaine, levobupivacaine, lidocaine, mepivacaine, oxethazaine, pramoxine, prilocaine, procaine, proparacaine, and ropivacaine; or (b) a narcotic analgesic selected from the group consisting of: alfentanil, alphaprodine, buprenorphine, butorphanol, codeine, codeine phosphate, cyclazocine, dextomoramide, dezocine, diamorphine, dihydrocodeine, dipianone, fedotozine, fentanyl, hydrocodone, hydromorphone, ketobemidone, levorphanol, meptazinol, methadone, methadyl acetate, morphine, nalbuphine, norpropoxyphene, noscapine, oxycodone, oxymorphone, paregoric, pentazocine, pethidine, phenazocine, piritramide, propoxyphene, remifentanil, sufentanil, tilidine, and tramadol; or (c) a nonnarcotic analgesic selected from the group consisting of: aminosalicylic sodium, balsalazide, choline salicylate, mesalazine, olsalazine, para-amino salicylic acid, salicylic acid, salicylsalicylic acid, and sulphasalazine, ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and naproxen.