Methods and Devices for Sustained In-Vivo Release Of an Active Agent

Abstract

The present invention includes methods and devices for providing sustained in-vivo release of an active agent to a subject. In some aspects, such release may be achieved by reacting an active agent in-vivo with a depot forming agent in order to form a sustained release active agent depot inside the subject. The depot can then release the active agent over a sustained period of time.

1 . A method of providing sustained in-vivo release of an active agent in a subject, comprising:
 delivering the active agent noninvasively to the subject;   delivering a depot forming agent noninvasively to the subject, wherein the active agent and the depot forming agent are delivered from a single device;   reacting the active agent with the depot forming agent inside the subject to cause a reduction in solubility of the active agent to form a precipitate the active agent and thus create an active agent sustained release depot; and   allowing the depot to release the active agent over a sustained period of time.   
     
     
         2 . The method of  claim 1 , wherein the reaction is an ionic association between the active agent and the depot forming agent. 
     
     
         3 . The method of  claim 2 , wherein the depot forming agent is polyvalent and has multiple charges that are opposite to charges carried by the active agent. 
     
     
         4 . The method of  claim 3 , wherein the precipitate of depot forming agent and active agent has a ratio of depot agent to active agent of from about 4:1 to about 1:4. 
     
     
         5 . The method of  claim 1 , wherein the reaction cleaves a portion of the active agent, thus lowering the aqueous solubility of the active agent. 
     
     
         6 . The method of  claim 5 , wherein the depot forming agent is an enzyme. 
     
     
         7 . The method of  claim 1 , wherein the depot forming agent is administered either prior to, concurrently with, or following the active agent. 
     
     
         8 . The method of  claim 7 , wherein the depot forming agent is administered concurrently with the active agent. 
     
     
         9 . The method of  claim 1 , wherein the active agent in the sustained release depot comprises a crystal, a semi-solid, or a combination thereof. 
     
     
         10 . The method of  claim 1 , wherein the active agent is a member selected from a group consisting essentially of analeptic agents, analgesic agents, anesthetic agents, antiasthmatic agents, antiarthritic agents, anticancer agents, anticholinergic agents, anticonvulsant agents, antidepressant agents, antidiabetic agents, antidiarrheal agents, antiemetic agents, antihelminthic agents, antihistamines, antihyperlipidemic agents, antihypertensive agents, anti-infective agents, antiinflammatory agents, antimigraine agents, antineoplastic agents, antiparkinsonism drugs, antipruritic agents, antipsychotic agents, antipyretic agents, antispasmodic agents, antitubercular agents, antiulcer agents, antiviral agents, anxiolytic agents, appetite suppressants, attention deficit disorder and attention deficit hyperactivity disorder drugs, cardiovascular agents including calcium channel blockers, antianginal agents, central nervous system (“CNS”) agents, beta-blockers and antiarrhythmic agents, central nervous system stimulants, diuretics, genetic materials, hormonolytics, hypnotics, hypoglycemic agents, immunosuppressive agents, muscle relaxants, narcotic antagonists, nicotine, nutritional agents, parasympatholytics, peptide drugs, psychostimulants, sedatives, steroids, smoking cessation agents, sympathomimetics, tranquilizers, vasodilators, β-agonists, and tocolytic agents, and mixtures thereof. 
     
     
         11 . The method of  claim 1 , wherein the active agent is a member selected from the group consisting essentially of steroids, aminosteroids, antibacterials, antivirals, antifungals, antiprotozoals, antimetabolites, VEGF inhibitors, ICAM inhibitors, antibodies, protein kinase C inhibitors, chemotherapeutic agents, immunosuppressive agents, neuroprotective agents, analgesic agents, nucleic acid derivatives, aptamers, proteins, enzymes, peptides, polypeptides, and mixtures thereof. 
     
     
         12 . The method of  claim 1 , wherein the active agent is a member selected from the group consisting of hydromorphone, dexamethasone phosphate, amikacin, oligonucleotides, F ab  peptides, PEG-oligonucleotides, salicylate, tropicamide, methotrexate, 5-fluorouracil, squalamine, triamcinolone acetonide, diclofenac, combretastatin A4, mycophenolate mofetil, mycophenolic acid, and mixtures thereof. 
     
     
         13 . The method of  claim 1 , wherein the active agent is a prodrug. 
     
     
         14 . The method of  claim 13 , wherein the prodrug is a member selected from the group consisting essentially of the derivatives of steroids, antibacterials, antivirals, antifungals, antiprotozoals, antimetabolites, VEGF inhibitors, ICAM inhibitors, antibodies, protein kinase C inhibitors, chemotherapeutic agents, immunosuppressive agents, neuroprotective agents, analgesic agents, nucleic acid derivatives, aptamers, proteins, enzymes, peptides, polypeptides, and mixtures thereof. 
     
     
         15 . The method of  claim 14 , wherein the steroid derivative is triamcinolone acetonide phosphate. 
     
     
         16 . The method of  claim 1 , wherein the active agent is used to treat an eye disease selected from the group consisting of macular edema, age related macular degeneration, anterior, intermediate, and posterior uveitis, HSV retinitis, diabetic retinopathy, bacterial, fungal, or viral endophthalmitis, eye cancers, glioblastomas, glaucoma, and glaucomatous degradation of the optic nerve. 
     
     
         17 . The method of  claim 1 , wherein the active agent and the depot forming agent are delivered into an eye of the subject. 
     
     
         18 . The method of  claim 1 , wherein the depot forming agent is a member selected from the group consisting essentially of inorganic ions, organic cations, organic anions, and ionic pharmaceutical excipients. 
     
     
         19 . The method of  claim 1 , wherein the depot forming agent is a member selected from the transition metals in the periodic tables. 
     
     
         20 . The method of  claim 1 , wherein the depot forming agent is an ion selected from the group consisting of: Ca 2+ , Sn 2+ , Fe 2+ , Fe 3+ , Mn 2+ , Mg 2+ , Zn 2+ , NH 4   + , PO 4   3− , CO 3   2− , SO 4   2− . 
     
     
         21 . The method of  claim 1 , wherein the depot forming agent has an adequate ionic charge for both effective iontophoretic delivery and effectively reacting with the active agent to form the sustained release depot. 
     
     
         22 . The method of  claim 1 , wherein the depot is a gel created by a complex of a triamcinolone acetonide phosphate active agent and a Ca 2+  depot forming agent. 
     
     
         23 . The method of  claim 1 , wherein the depot forming agent is a catalyst, a polymerization initiator, a pegylating agent, or a combination thereof. 
     
     
         24 . The method of  claim 1 , wherein the depot forming agent is a solvent. 
     
     
         25 . The method of  claim 1 , wherein the depot forming agent is an active agent used in the treatment of eye diseases. 
     
     
         26 . The method of  claim 25 , wherein the depot forming agent is an aminosteroid. 
     
     
         27 . The method of  claim 26 , wherein the aminosteroid is squalamine. 
     
     
         28 . The method of  claim 25 , wherein the depot forming agent is a derivative of triamcinolone acetonide. 
     
     
         29 . The method of  claim 1 , further comprising restricting in-vivo movement of the active agent for a time sufficient to allow reaction with the depot forming agent and formation of the sustained release depot. 
     
     
         30 . The method of  claim 29 , wherein restricting the in-vivo movement is accomplished by constriction of blood vessels exiting an area in which active agent precipitation occurs, wherein the constriction of blood vessels is induced by administration of a vasoconstricting agent. 
     
     
         31 . The method of  claim 30 , wherein the vasoconstricting agent is a member selected from the group consisting of α-agonists such as naphazoline, and tetrahydrozoline, sympathomimetics such as phenylethylamine, epinephrine, norepinephrine, dopamine, dobutamine, colterol, ethylnorepinephrine, isoproterenol, isoetharine, metaproterenol, terbutaline, metearaminol, phenylephrine, tyramine, hydroxyamphetamine, ritrodrine, prenalterol, methoxyamine, albuterol, amphetamine, methamphetamine, benzphetamine, ephedrine, phenylpropanolamine, methentermine, phentermine, fenfluramine, propylhexedrine, diethylpropion, phenmetrazine, and phendimetrazine. 
     
     
         32 . The method of  claim 1 , wherein the non-invasive delivery is either iontophoretic, sonophoretic, or electroporation administration. 
     
     
         33 . The method of  claim 32 , wherein the non-invasive administration is iontophoretic. 
     
     
         34 . The method of  claim 1 , further comprising enhancing delivery of either the active agent, or the depot forming agent, or both the active agent and the depot forming agent with a permselective material. 
     
     
         35 . The method of  claim 17 , wherein the active agent is delivered to one side of the eye, and the depot forming agent is delivered to an opposite side of the eye. 
     
     
         36 . The method of  claim 17 , wherein the depot forming agent and the active agent are delivered side-by-side next to each other in the eye. 
     
     
         37 . A medicinal depot formulation in a subject formed by the method of  claim 1 , comprising:
 a mass of active agent in precipitated form that becomes solubilized and releases active agent over a sustained period of time.