Injectable slurries and methods of manufacturing and using the same

Abstract

One aspect of the invention provides a slurry comprising: a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and a biocompatible surfactant. Another aspect of the invention provides a slurry including: a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; a biocompatible surfactant; and a foam comprising a plurality of gas bubbles. Another aspect of the invention provides a slurry including: a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and a biocompatible excipient. Another aspect of the invention provides a slurry including: a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and a lipolytic agent.

1 . A slurry comprising:
 a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and   a biocompatible surfactant.   
     
     
         2 . The slurry of  claim 1 , wherein the plurality of sterile ice particles have a largest cross-sectional dimension less than a value selected from the group consisting of: about 1.25 mm, about 1 mm, about 0.9 mm, about 0.8 mm, about 0.7 mm, about 0.6 mm, about 0.5 mm, about 0.4 mm, about 0.3 mm, about 0.2 mm, and about 0.1 mm. 
     
     
         3 . The slurry of  claim 1 , wherein the biocompatible surfactant is one or more selected from the group consisting of: a solvent, a detergent, a wetting agent, an emulsifier, a foaming agent, and a dispersant. 
     
     
         4 . The slurry of  claim 1 , wherein the biocompatible surfactant is one or more selected from the group consisting of: anionic, cationic, amphoteric, and nonionic. 
     
     
         5 . The slurry of  claim 1 , wherein the biocompatible surfactant is glycerol. 
     
     
         6 . The slurry of  claim 1 , wherein the biocompatible surfactant is urea. 
     
     
         7 . The slurry of  claim 1 , wherein the plurality of ice particles constitute between about 0.1% and about 75% of the slurry by weight. 
     
     
         8 . The slurry of  claim 1 , wherein the plurality of ice particles constitute a percentage by weight selected from the group consisting of: between about 0.1% and 1%, between about 1% and 10%, between about 10% and about 20%, between about 20% and about 30%, between about 30% and about 40%, between about 40% and about 50%, between about 50% and about 60%, between about 60% and about 70%, and greater than about 50%. 
     
     
         9 . The slurry of  claim 1 , wherein the plurality of ice particles constitute between about 0.1% and about 50% of the slurry by weight. 
     
     
         10 . The slurry of  claim 1 , further comprising:
 a therapeutic compound.   
     
     
         11 . The slurry of  claim 1 , wherein the therapeutic compound is selected from the group consisting of: an anesthetic and an analgesic. 
     
     
         12 . The slurry of  claim 1 , wherein the therapeutic compound is a water-soluble anesthetic. 
     
     
         13 . The slurry of  claim 1 , wherein the therapeutic compound is selected from the group consisting of: prilocaine, bupivacaine, prilocaine, tetracaine, procaine, mepivicaine, etidocaine, lidocaine, QX-314, and a nonsteroidal anti-inflammatory drugs (NSAID). 
     
     
         14 . The slurry of  claim 1 , wherein the therapeutic compound is a vasoconstrictor. 
     
     
         15 . The slurry of  claim 14 , wherein the vasoconstrictor is selected from the group consisting of: epinephrine, norepinephrine, a selective adrenergic agonist, a nonselective adrenergic agonist, and a corticosteroid. 
     
     
         16 . The slurry of  claim 1 , further comprising:
 one or more selected from the group consisting of: microbubbles, nanobubbles, and biodegradable solids.   
     
     
         17 . The slurry of  claim 1 , further comprising:
 a toxin.   
     
     
         18 . The slurry of  claim 17 , wherein the toxin is ethanol. 
     
     
         19 . The slurry of  claim 1 , wherein the slurry is hypertonic. 
     
     
         20 . The slurry of  claim 1 , wherein the slurry is hypotonic. 
     
     
         21 . The slurry of  claim 1 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         22 . The slurry of  claim 1 , wherein the slurry has a mean temperature of about +5° C. or lower. 
     
     
         23 . A slurry comprising:
 a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm;   a biocompatible surfactant; and   a foam comprising a plurality of gas bubbles.   
     
     
         24 . The slurry of  claim 23 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         25 . A slurry comprising:
 a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and   a biocompatible excipient.   
     
     
         26 . The slurry of  claim 25 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         27 . A slurry comprising:
 a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and   a lipolytic agent.   
     
     
         28 . The slurry of  claim 27 , wherein the lipolytic agent is a detergent. 
     
     
         29 . The slurry of  claim 28 , wherein the detergent is deoxycholate. 
     
     
         30 . The slurry of  claim 27 , wherein the lipolytic agent is an alcohol. 
     
     
         31 . The slurry of  claim 27 , wherein the lipolytic agent is an organic solvent. 
     
     
         32 . The slurry of  claim 27 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         33 . A method of treating a subject, the method comprising:
 injecting a slurry comprising a plurality of sterile ice particles having a largest cross-sectional dimension less that about 1.5 mm and a biocompatible surfactant into a treatment region of the subject.   
     
     
         34 . The method of  claim 33 , wherein the treatment region is selected from the group consisting of: proximate to a nerve, proximate to subcutaneous adipose tissue, proximate to breast tissue, proximate to visceral fat, fatty tissue proximate to the pharynx, fatty tissue proximate to the palate, fatty tissue proximate to the tongue, proximate to a spinal cord lipoma, proximate to a lipomyelomeningocele, proximate to visceral fat, proximate to lipomastia, proximate to a tumor, proximate to cardiac tissue, proximate to pericardial fat, and proximate to epicardial fat. 
     
     
         35 . The method of  claim 33 , wherein the treatment region comprises one or more tissues selected from the group consisting of: connective, epithelial, neural, joint, cardiac, adipose, hepatic, renal, vascular, cutaneous, and muscle. 
     
     
         36 . The method of  claim 33 , further comprising:
 measuring a temperature of the slurry prior to injection.   
     
     
         37 . The method of  claim 33 , wherein the slurry is injected via gravity flow. 
     
     
         38 . The method of  claim 33 , wherein the slurry is injected via pressure injection. 
     
     
         39 . The method of  claim 33 , wherein the slurry is injected through one or more selected from the group consisting of: a syringe, a cannula, a catheter, and tubing. 
     
     
         40 . The method of  claim 33 , further comprising:
 pre-cooling the treatment region prior to the injecting step.   
     
     
         41 . The method of  claim 33 , further comprising:
 applying energy adjacent to the target tissue.   
     
     
         42 . The method of  claim 33 , further comprising:
 applying suction to the treatment region to remove melted slurry.   
     
     
         43 . The method of  claim 33 , wherein the injecting step comprises injecting a sufficient volume of the slurry to cause tumescent swelling of the treatment region. 
     
     
         44 . The method of  claim 33 , wherein the injecting step is repeated a plurality of times. 
     
     
         45 . The method of  claim 33 , further comprising:
 calculating a desired amount of slurry to be injected based on a desired amount of disruption to the treatment region.   
     
     
         46 . The method of  claim 33 , wherein the slurry cools the treatment region adjacent to an injection site at a rate greater in magnitude than about −2° C. per minute. 
     
     
         47 . The method of  claim 33 , wherein the method thickens septa. 
     
     
         48 . The method of  claim 33 , further comprising:
 mixing the slurry with relatively warmer liquid prior to the injecting step.   
     
     
         49 . The method of  claim 33 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         50 . The method of  claim 33 , wherein the slurry is hypotonic relative to the treatment region. 
     
     
         51 . The method of  claim 33 , wherein the slurry is isotonic relative to the treatment region. 
     
     
         52 . The method of  claim 33 , wherein the slurry is hypertonic relative to the treatment region. 
     
     
         53 . A method of treating a subject, the method comprising:
 injecting the slurry comprising a plurality of sterile ice particles having a largest cross-sectional dimension less that about 1.5 mm and a biocompatible surfactant having a temperature and cooling capacity sufficient to non-selectively disrupt tissue into a treatment region of the subject.   
     
     
         54 . The method of  claim 53 , wherein the treatment region is selected from the group consisting of: a prostate, a kidney, a heart, and a fibroadenoma. 
     
     
         55 . The method of  claim 53 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         56 . The method of  claim 53 , wherein the slurry is hypotonic relative to the treatment region. 
     
     
         57 . The method of  claim 53 , wherein the slurry is isotonic relative to the treatment region. 
     
     
         58 . The method of  claim 53 , wherein the slurry is hypertonic relative to the treatment region. 
     
     
         59 . A method of treating a subject, the method comprising:
 injecting a slurry into a treatment region of the subject selected from the group consisting of: proximate to a nerve, proximate to subcutaneous adipose tissue, proximate to breast tissue, proximate to visceral fat, fatty tissue proximate to the pharynx, fatty tissue proximate to the palate, fatty tissue proximate to the tongue, proximate to a spinal cord lipoma, proximate to a lipomyelomeningocele, proximate to visceral fat, proximate to lipomastia, proximate to a tumor, proximate to cardiac tissue, proximate to pericardial fat, and proximate to epicardial fat.   
     
     
         60 . The method of  claim 59 , wherein the slurry includes an ionic component. 
     
     
         61 . The method of  claim 59 , wherein the slurry has a temperature and cooling capacity sufficient to non-selectively disrupt tissue into a treatment region of the subject. 
     
     
         62 . The method of  claim 59 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         63 . A method of preparing a slurry, the method comprising:
 freezing a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm in one or more micromolds; and   mixing the plurality of sterile ice particles with one or more biocompatible liquids.   
     
     
         64 . The method of  claim 63 , wherein the plurality of sterile ice particles have a substantially uniform shape. 
     
     
         65 . The method of  claim 63 , wherein the one or more micromolds are fabricated from one or more materials selected from the group consisting of: polymers, plastics, elastomers, silicons, silicones, and metals. 
     
     
         66 . The method of  claim 63 , further comprising:
 applying mechanical strain, stress waves, shock waves, or centripetal force to remove the plurality of sterile ice particles from the one or more micromolds.   
     
     
         67 . The method of  claim 63 , wherein the slurry has a mean temperature selected from the group consisting of: about +10° C., about +9° C., about +8° C., about +7° C., about +6° C., about +5° C., about +4° C., about +3° C., about +2° C., about +1° C., about 0° C., about −1° C., about −2° C., about −3° C., about −4° C., about −5° C., about −6° C., about −7° C., about −8° C., about −9° C., about −10° C., about −11° C., about −12° C., about −13° C., about −14° C., about −15° C., between about −15° C. and about −25° C., between about −25° C. and about −50° C., and between about −50° C. and about −75° C. 
     
     
         68 . A slurry comprising:
 a plurality of sterile ice particles having a largest cross-sectional dimension less than about 1.5 mm; and   an ionic component selected from the group consisting of: hydrogen ions, lactate, phosphate, zinc ions, sulfur ions, nitrate, ammonium, hydroxide, iron ions, barium ions.