WO2008073938A2 - Perfusive organ hemostasis - Google Patents

Perfusive organ hemostasis Download PDF

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Publication number
WO2008073938A2
WO2008073938A2 PCT/US2007/087079 US2007087079W WO2008073938A2 WO 2008073938 A2 WO2008073938 A2 WO 2008073938A2 US 2007087079 W US2007087079 W US 2007087079W WO 2008073938 A2 WO2008073938 A2 WO 2008073938A2
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WIPO (PCT)
Prior art keywords
transient gel
transient
polymer
certain embodiments
poloxamer
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PCT/US2007/087079
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English (en)
French (fr)
Inventor
Jean-Marie Vogel
James A. Wilkie
Peter N. Madras
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Pluromed Inc
Lahey Hospital and Medical Center
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Pluromed Inc
Lahey Hospital and Medical Center
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Priority to EP07865497.7A priority Critical patent/EP2094169A4/en
Priority to JP2009541532A priority patent/JP2010512230A/ja
Priority to CN200780051223A priority patent/CN101677822A/zh
Publication of WO2008073938A2 publication Critical patent/WO2008073938A2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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Definitions

  • Nephron-Sparing Surgery in itself may prove to be suitable in a variety of contexts.
  • NSS renal cell carcinoma
  • RCC renal cell carcinoma
  • Recent advances in preoperative staging, specifically modern imaging techniques, and improvements in surgical techniques have made partial nephrectomy an attractive alternative to radical nephrectomy in selected patients.
  • NSS is more clearly indicated for cases in which a radical nephrectomy would render the patient anephric with a subsequent immediate need for dialysis.
  • Synchronous bilateral tumors, tumors in a solitary kidney, or the presence of a poorly functional contralateral renal unit are generally absolute indications for NSS.
  • Partial nephrectomy may also be considered the treatment of choice for certain benign conditions and localized pathology of the kidney.
  • A. C. Novick "The role of nephron-sparing surgery for renal cell carcinoma in patients with a normal contralateral kidney," Advan Urol 1996, 9, 1. It allows for optimal surgical treatment and, at the same time, obviates over-treatment and nephron loss when possible and necessary.
  • Examples of potentially more benign indications include traumatic irreversible injury to a localized portion of the kidney and removal of a benign renal tumor such as an oncocytoma, angiomyolipoma, or multilocular cyst.
  • Other indications include an obstructed atrophied segment of a duplicated kidney, calculus disease of a renal segment with impaired drainage, and, rarely, renovascular hypertension with identifiable noncorrectible branch renal artery disease.
  • R.G. Uzzo and A.C. Novick "Nephron sparing surgery for renal tumors: indications, techniques and outcomes," J. of Urol. 2001, 166, 6-18.
  • NSS neurosthelial styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene, renethelial styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styren
  • Postoperative renal insufficiency typically results from a combination of intraoperative ischemia and loss of functioning renal parenchyma.
  • the extent of renal insufficiency varies, and its degree is reflected by the increase of retention parameters such as creatinine, blood urea, and potassium.
  • Severe renal insufficiency may require temporary dialysis. If the compensatory hypertrophy of the remnant kidney tissue cannot compensate for the loss of renal function, a permanent insufficiency requiring permanent dialysis may result.
  • the main steps of conventional partial nephrectomy include initiating diuresis with intravenous mannitol and a loop diuretic (e.g., furosemid) intraoperatively, with generous hydration before any interruption in the renal circulation.
  • a loop diuretic e.g., furosemid
  • Mannitol is infused before anticipated renal occlusion.
  • This agent not only induces osmotic diurisis but also is a free radical scavenger that can minimize ischemic insult from arterial clamping and the ultimate risk of postoperative acute tubular necrosis.
  • partial nephrectomy an incision is made of either the bilateral subcostal or thoracoabdominal type. After opening the abdomen, the colon is moved to expose the kidney. The renal artery is temporarily clamped to reduce bleeding. Typically, the renal artery is occluded with an atraumatic vascular Bulldog clamp. The renal vein may remain non-occluded since retrograde profusion of the kidney might minimize the chance for acute tubular necrosis postoperatively.
  • the kidney is dissected from the surrounding tissue from outside the renal fascia.
  • the tumor is removed with a margin of normal tissue.
  • the calyxes and renal pelvis that have been cut through are carefully closed with sutures.
  • the cut end of the kidney is covered with fat, fascia or peritoneum.
  • the clamp on the renal artery is removed and all bleeding is controlled prior to the incision being closed. Issues with Current Hemostatic Approaches.
  • One of the main drawbacks associated with the conventional partial nephrectomy method is that clamping of the renal artery causes ischemia of the whole kidney. Although the ischemia is typically transient it may nevertheless lead to renal insufficiency if the arterial clamp time is extended.
  • Clamping and subsequent release of the renal artery may hence potentially lead not only to ischemia injury but also to reperfusion injuries.
  • the goal is to use a renal tourniquet in order to localize the ischemia to the tissue which is to be removed and its immediate periphery.
  • reducing ischemia to the remainder of the kidney is theoretically appealing, attempts at clamping tumor-adjacent kidney tissue instead of the renal artery during partial nephrectomy have proven to be unsuccessful due to unreliable hemostasis during surgery.
  • problems associated with attempts at clamping kidney tissue instead of the kidney arteries may be, at least partially, imputable to the use of conventional vascular clamps to perform the tissue clamping operation.
  • conventional vascular clamps typically include a pair of pivoting arms with a clamping jaw rigidly attached to a distal end of each pivoting arm. The process of clamping generates loci of high pressure far in excess of the pressure in the blood vessel itself.
  • Conventional clamps such as the Fogarty clamp, the DeBakey "Atraugrip", the Bulldog clamp or Pott's and Satinsky's peripheral vascular clamps exert relatively high pressures, in some cases up to nine bars on clamped blood vessels.
  • tissue sealants have been adapted or developed for laparoscopic surgery and purposed especially for nephron-sparing surgery.
  • tissue sealants The use of tissue sealants in partial nephrectomy allows for a fast parenchyma, vascular, and collecting system repair and reduces not only the overall operative time but particularly the warm ischemia time. Therefore, the negative impact on the renal function of temporary vascular clamping can be reduced, of pivotal importance especially in patients with a solitary kidney or with impaired renal function.
  • tissue sealants are the only adequate alternatives for bleeding control of the cut renal surface, and their use as unique hemostatic agents is adequate in cases of small peripheral lesions.
  • Sealants can be divided into two categories: non-biologic and biologic. Among the non-biologic glues, the best known is probably 2-octyl-cyanoacrylate.
  • biologic sealants include thrombin or fibrinogen or both. They are the terminal product of the clotting process and their use determines a fibrin matrix over the site of apposition. Probably the best known biologic sealants are fibrin glues (Tissuecol, Crosseal, Tisseel).
  • Gelatin matrix hemostatic sealant (FloSeal) is a more recent solution widely used as a hemostatic sealant. It is a combination of a bovine gelatin-based matrix with a bovine-derived concentrated thrombin component. This viscous collagen matrix requires active bleeding to be activated and work, promoting coagulation and hemostasis at the site of bleeding; it requires 1-2 minutes of delicate compression on the cut edge of the parenchyma after its apposition.
  • inventive compositions, methods and kits provided herein serve to control bleeding through the use of an internal occluder based on polymeric solutions.
  • an internal occluder based on polymeric solutions.
  • herein is disclosed the use of reverse thermosensitive polymers in nephron- sparing surgeries.
  • the renal artery leading to a diseased kidney is infused with a transient reverse thermosensitive gel. This has been shown to lead to cessation of blood flow within the renal parenchyma. It appears that, with the appropriate injection rate, the polymer flows downstream to occlude small, intra-renal vessels on both the arterial and venous sides of the circulation. Remarkably, this produces a completely bloodless surgical field, allowing speedy resection.
  • the flow gradually resumes, with no apparent adverse consequences to the kidney.
  • return of blood flow may be accelerated by cooling the kidney.
  • the inventive perfusive organ hemostasis just described can be used to simplify or to enable other organ surgeries or interventional procedures.
  • the inventive perfusive organ hemostasis just described can be used to simplify or to enable liver surgery, prostate surgery, brain surgery, surgery of the uterus, spleen surgery and any surgery on any highly vascularized organs.
  • the compositions, methods and kits described for perfusive organ hemostasis can be used for intervention on scleroses arteries, intervention on calcified vessels, as well as many other surgical and interventional uses.
  • Figure 1 depicts occlusion using internal vessel occluder during partial nephrectomy in pigs at 15 minutes (a), 30 minutes (b), and 50 minutes (c). Fifteen minutes after injection the kidney is completely avascular and no bleeding is observed from the cut edges. Thirty minutes after injection, kidney perfusion is returning and not a drop of blood is observed. Fifty minutes after injection, the kidney has returned to normal; this was verified by pathology reports.
  • Figure 2 depicts a graph showing the amount of blood collected in 15 minutes during coronary anastomosis in four pigs treated either with tape or a combination of tape and a polymer composition of the invention (i.e., 20% solution of poloxamer 407 in saline).
  • Figure 3 depicts the use of the polymers of the invention (e.g., 20% solution of poloxamer 407) in a bypass surgery.
  • the polymeric material is easy to inject (a), creating a pristine bloodless surgical field (b), allowing easy sewing (c), and disappears after use (d).
  • Figure 4 depicts a graph of viscosity as a function of temperature for various solutions of purified poloxamer 407.
  • Figure 5 depicts a table (Table 1) showing the purification of poloxamer 407; and a table (Table 2) showing the gelation temperature of selected reverse thermosensitive polymers in saline.
  • Table 1 shows the purification of poloxamer 407; and a table (Table 2) showing the gelation temperature of selected reverse thermosensitive polymers in saline.
  • Table 1 shows a viscosity of a 25% solution measured at 30 0 C using a cone and plate viscometer.
  • Surgically removing only the morbid part of a diseased kidney instead of removing the entire kidney is beneficial for overall long-term kidney function.
  • the technical hurdles limiting the adoption of this approach are the ability to control bleeding during the surgery and the need to reduce warm ischemia time.
  • a bloodless field is also vital to the success of laparoscopic minimally invasive techniques.
  • perfusive organ hemostasis to control bleeding during the procedure by filling the kidney with a biocompatible gel which completely prevents bleeding and makes the surgery easier, potentially reducing the duration of the procedure.
  • the inventive perfusive organ hemostasis described can be used to simplify or to enable other organ surgeries or interventional procedures.
  • the inventive perfusive organ hemostasis described can be used to simplify or to enable liver surgery, prostate surgery, brain surgery, surgery of the uterus, spleen surgery, as well as any surgery on any highly vascularized organs.
  • the compositions, methods and kits described for perfusive organ hemostasis can be used for intervention on sclerotic arteries, intervention on calcified vessels, as well as many other surgical and interventional uses.
  • compositions, methods and kits for controlling bleeding through the use of an internal occluder based on polymeric solutions are reverse thermosensitive polymeric solutions.
  • these solutions are reverse thermosensitive polymeric solutions.
  • a reverse thermosensitive polymer solution is a liquid and as the temperature increases to body temperature, its viscosity increases several orders of magnitude to the consistency of a hard gel, leading to occlusion of the vessels. Cooling the occlusion site lowers the viscosity back to that of the liquid, dissolving the gel in blood and reestablishing blood flow.
  • calcified arteries may be gently occluded, stopping the arterial and venous blood supply to an organ.
  • this occlusion will prevent bleeding and provide a surgeon with a bloodless surgical field.
  • the bloodless surgical field should reduce the operating time required for a surgery. In certain surgeries, the operating time could be reduced to such an extent that warm ischemia time would be drastically reduced.
  • the gel's working principle is based on the reverse thermosensitive properties of the polymer.
  • the polymeric solution is a liquid.
  • the viscosity of the solution rapidly increases several orders of magnitude to the consistency of a hard gel. Cooling the occlusion site, simply by the application of ice, lowers the viscosity back to that of a liquid, dissolving the gel in blood and reestablishing blood flow.
  • the gel has been developed for applications in anastomosis such as Off-Pump Bypass surgery (OPCAB), hemodialysis access, and tibial anastomosis.
  • OPCAB Off-Pump Bypass surgery
  • the transient gels of the invention offer great advantages for intraoperative hemostasis, by allowing a solution to perfuse into and solidify in the both the arterial and venous sides of the organ's circulation, thereby completely or substantially occluding the blood supply of the organ.
  • the use of reverse thermosensitive polymers in nephron-sparing surgery In certain embodiments, the renal artery leading to the diseased kidney is infused with the reverse thermosensitive gel. This has been shown to lead to cessation of blood flow within the renal parenchyma. It appears that, with the appropriate injection rate, the polymer flows downstream to occlude small, intra-renal vessels on both the arterial and venous sides of the circulation.
  • the polymer used in some of the Exemplification has a lower than optimal transition temperature for a solid organ.
  • temperatures during the surgery may be higher than in exposed arteries where the company has greater experimental experience.
  • a polymer solution with a higher transition temperature may be superior to the present formulation for solid organ applications.
  • Several such higher transition temperature polymer solutions are disclosed herein (see Figure 5, Table 2).
  • the rate/volume of injection may be used to control expected downstream ischemic time.
  • an injection system that does not unduly increase the procedural time by requiring a long dissection of the artery or requiring additional surgery to repair the artery at the injection site is claimed herein.
  • the polymeric gel in order to adequately occlude a kidney for partial nephrectomy, for example, the polymeric gel must flow into the renal artery and then into the vascular structure of the kidney. The gel may be injected into either the renal artery or in the aorta immediately adjacent to the renal artery. After application the surgeon must close the injection site to prevent post operative bleeding.
  • patients with diseased kidneys typically have calcified arteries, so a smaller puncture site is desirable.
  • the tip of the injector must enter the renal artery to direct the flow of gel into the kidney.
  • a surgeon must weigh certain options when choosing an injection site: 1) the degree of difficulty in obtaining access to the renal artery, 2) the degree of difficulty in successfully cannulating a calcified vessel and subsequently closing the puncture site, and 3) in the event that the aorta is preferable, the ease with which the injector tip can be directed to the renal artery.
  • One must also seek to minimize any time or effort spent to dissect a vessel prior to injection. Further, it may be advantageous to leave the injection system in place during the partial nephrectomy in the event that an additional dose of the gel is needed, and as a conduit to inject saline solution if needed for earlier dissolution of the gel.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • sustained release When used with respect to a therapeutic agent or other material, the term "sustained release" is art-recognized.
  • a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time.
  • polystyrene resin denotes a symmetrical block copolymer, consisting of a core of PPG polyoxyethylated to both its terminal hydroxyl groups, i.e., conforming to the interchangable generic formula (PEG) X -(PPG) Y -(PEG) X and (PEO) x -(PPO) ⁇ -(PEO) x .
  • PEG interchangable generic formula
  • polyxamine denotes a polyalkoxylated symmetrical block copolymer of ethylene diamine conforming to the general type [(PEG) x -(PPG) ⁇ ] 2 -NCH 2 CH 2 N-[(PPG) ⁇ - (PEG) ⁇ ] 2 .
  • Each Poloxamine name is followed by an arbitrary code number, which is related to the average numerical values of the respective monomer units denoted by X and Y.
  • Reverse thermosensitive polymer refers to a polymer that is soluble in water at ambient temperature, but at least partially phase-separates out of water at physiological temperature.
  • Reverse thermosensitive polymers include, for example, poloxamer 407, poloxamer 188, Pluronic® F127, Pluronic® F68, poly(N- isopropylacrylamide), poly(methyl vinyl ether), poly(N-vinylcaprolactam); and certain poly(organophosphazenes). See: B. H. Lee, et al.
  • reversibly gelling and "reverse thermosensitive” refer to the property of a polymer wherein gelation takes place upon an increase in temperature, rather than a decrease in temperature.
  • transition temperature refers to the temperature or temperature range at which gelation of an reverse thermosensitive polymer occurs.
  • degradable refers to having the property of breaking down or degrading under certain conditions, e.g., by dissolution.
  • polydispersity index refers to the ratio of the "weight average molecular weight” to the "number average molecular weight” for a particular polymer; it reflects the distribution of individual molecular weights in a polymer sample.
  • weight average molecular weight refers to a particular measure of the molecular weight of a polymer.
  • the weight average molecular weight is calculated as follows: determine the molecular weight of a number of polymer molecules; add the squares of these weights; and then divide by the total weight of the molecules.
  • number average molecular weight refers to a particular measure of the molecular weight of a polymer.
  • the number average molecular weight is the common average of the molecular weights of the individual polymer molecules. It is determined by measuring the molecular weight of n polymer molecules, summing the weights, and dividing by n.
  • biocompatible refers to having the property of being biologically compatible by not producing a toxic, injurious, or immunological response in living tissue.
  • cold-packs are two containers containing chemicals separated by a frangible seal. When the seal is broken, as the contents from the separate containers begin to react, energy is absorbed from the surroundings creating a cooling effect.
  • chemicals which can be mixed in a cold pack are ammonium nitrate and water.
  • the cold pack has two sealed bags, one inside the other.
  • the outer bag is made of thick strong plastic. It contains a ammonium nitrate and the second plastic bag.
  • the second (inner) bag is made of a thin weak plastic and contains water.
  • hemostasis refers to the stoppage of blood flow through a blood vessel or organ of the body. Hemostasis generally refers to the arrest of bleeding, whether it be by normal vasoconstriction (the vessel walls closing temporarily), by an abnormal obstruction (such as a plaque) or by coagulation or surgical means (such as ligation). As used herein, hemostasis is achieved by using a transient gel to create an obstruction.
  • Contemplated equivalents of the polymers, subunits and other compositions described above include such materials which otherwise correspond thereto, and which have the same general properties thereof (e.g., biocompatible), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of such molecule to achieve its intended purpose.
  • the compounds of the present invention may be prepared by, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • One aspect of the invention relates to compositions, methods and kits for partial nephrectomy which prevents renal surface bleeding and reduces warm ischemia time during the surgery, leading to improved patient outcomes.
  • partial nephrectomy is beneficial to the patient due to its kidney sparing effect, currently only about 12% of all nephrectomies are performed as partial nephrectomies. This is partially due to the technical difficulties encountered during the procedure.
  • B. A. Kletscher, et ah "Nephron-Sparing laparoscopic surgery: techniques to control the renal pedicle and manage parenchymal bleeding," J Endourol 1995, P, 23; and W. C.
  • the methods of the present invention combine the transient gel with the use of robotic and laparoscopic techniques in order to reduce blood loss and operative time with these minimally invasive techniques.
  • the perfusive organ hemostasis of the invention can also in other embodiments be used to simplify or to enable other organ surgeries or interventional procedures, such as liver surgery (e.g., a partial hepatectomy), prostate surgery (e.g., a full or partial prostatectomy), brain surgery, surgery of the uterus, spleen surgery and any surgery on any highly vascularized organs.
  • liver surgery e.g., a partial hepatectomy
  • prostate surgery e.g., a full or partial prostatectomy
  • brain surgery e.g., surgery of the uterus, spleen surgery and any surgery on any highly vascularized organs.
  • the compositions, methods and kits described for perfusive organ hemostasis can be used for intervention on scleroses arteries; intervention on calcified vessels; as well as for many other surgical and interventional uses.
  • the perfusive organ hemostasis of the invention may be accomplished by the use of polymers that form a gel inside the body and then dissolve or are dissolved, such as other reverse thermosensitive polymers and any polymer solution or combination of polymers that form a gel inside the body, being under the effect of temperature, pH, pressure, or as a result of a chemical or biological reaction.
  • the transient gels used in a method of the invention are crosslinkable polymers.
  • the transient gels can be generated in situ.
  • the transient gels can be non-tissue adhesive.
  • two solutions are injected separately (e.g., through a dual lumen catheter) into a biological lumen wherein they gel, forming a transient gel.
  • Said polymer solution may comprise an anionic polymer, a cationic polymer or a non-ionically crosslinkable polymer.
  • Such polymers may comprise one or more of the following: alginic acid, sodium alginate, potassium alginate, sodium gellan, potassium gellan, carboxy methyl cellulose, hyaluronic acid, and polyvinyl alcohol.
  • the cross-linking of the polymer to form a polymer gel may be achieved with anionic crosslinking ions, cationic crosslinking ions, or non-ionic crosslinking agents.
  • Crosslinking agents include, but are not limited to, one or more of the following: phosphate, citrate, borate, succinate, maleate, adipate, oxalate, calcium, magnesium, barium and strontium.
  • Exemplary pairings of polymers and crosslinkers include anionic polymer monomers with cations, such as, for example, alginates with calcium, barium or magnesium; gellans with calcium, magnesium or barium; or hyaluronic acid with calcium.
  • an exemplary pairing of a non-ionic polymer with a chemical crosslinking agent is a polyvinyl alcohol with borate (at a slightly alkaline pH).
  • the polymers used in the methods of the invention which become a gel at or about body temperature, can be administered in a liquid form.
  • the polymer composition of the invention may be a flexible or flowable material.
  • flowable is meant the ability to assume, over time, the shape of the space containing it at body temperature. This characteristic includes, for example, liquid compositions that are suitable for: injection with a manually operated syringe fitted with, for example, a needle; or delivery through a catheter.
  • flowable are highly viscous, gel-like materials at room temperature that may be delivered to the desired site by pouring, squeezing from a tube, or being injected with any one of the commercially available power injection devices that provide injection pressures greater than would be exerted by manual means alone.
  • the polymer used is itself flowable, the polymer composition of the invention, even when viscous, need not include a biocompatible solvent to be flowable, although trace or residual amounts of biocompatible solvents may be present.
  • the transient gel of the invention may be aqueous solution of one or more reverse thermosensitive polymers.
  • These polymer solutions are liquids below body temperature and gel at about body temperature.
  • the polymer solution is prepared external of the body, i.e., at a temperature below body temperature.
  • the polymer solution may be further chilled to prolong the time the gel stays in the liquid form upon introduction into the body.
  • a preferred temperature is about 10 °C below the gelation temperature of the polymer solution.
  • the transient gel used in connection with the methods of the invention may comprise a block copolymer with inverse thermal gelation properties.
  • the block copolymer can further comprise a polyoxyethylene-polyoxypropylene block copolymer, such as a biodegradable, biocompatible copolymer of polyethylene oxide and polypropylene oxide.
  • the reverse thermosensitive polymer can include one or more additives; for example, therapeutic agents may be added to the reverse thermosensitive polymers.
  • the block copolymers have molecular weights ranging from about 2,000 to about 1 ,000,000 Daltons, more particularly at least about 10,000 Daltons, and even more specifically at least about 25,000 Daltons or even at least about 50,000 Daltons. In certain embodiment, the block copolymers have a molecular weight between about 5,000 Daltons and about 30,000 Daltons. In certain embodiments, the molecular weight of the reverse thermosensitive polymer may be between about 1,000 and about 50,000 Daltons, or between about 5,000 and about 35,000 Daltons.
  • the molecular weight of a suitable reverse thermosensitive polymer may be, for example, between about 5,000 and about 25,000 Daltons, or between about 7,000 and about 20,000 Daltons.
  • Number-average molecular weight (M n ) may also vary, but will generally fall in the range of about 1,000 to about 400,000 Daltons, in some embodiments from about 1,000 to about 100,000 Daltons and, in other embodiments, from about 1,000 to about 70,000 Daltons. In certain embodiments, M n varies between about 5,000 and about 300,000 Daltons.
  • the polymer is in an aqueous solution.
  • typical aqueous solutions contain about 5% to about 30% polymer, preferably about 10% to about 25%.
  • the pH of the reverse thermosensitive polymer formulation administered to a mammal is, generally, about 6.0 to about 7.8, which are suitable pH levels for injection into the mammalian body.
  • the pH level may be adjusted by any suitable acid or base, such as hydrochloric acid or sodium hydroxide.
  • the reverse thermosensitive polymers of the invention are poloxamers or poloxamines.
  • Pluronic® polymers have unique surfactant abilities and extremely low toxicity and immunogenic responses. These products have low acute oral and dermal toxicity and low potential for causing irritation or sensitization, and the general chronic and sub-chronic toxicity is low.
  • Pluronic® polymers are among a small number of surfactants that have been approved by the FDA for direct use in medical applications and as food additives. See: BASF (1990) Pluronic® & Tetronic® Surfactants, BASF Co., Mount Olive, NJ.. Recently, several Pluronic® polymers have been found to enhance the therapeutic effect of drugs, and the gene transfer efficiency mediated by adenovirus. K. L.
  • Nonionic Surfactants polyoxyalkylene block copolymers, Vol. 60. Nace VM, Dekker M (editors), New York, 1996. 280 pp. Their surfactant properties have been useful in detergency, dispersion, stabilization, foaming, and emulsification.
  • Poloxamer 407 is a biocompatible polyoxypropylene-polyoxyethylene block copolymer having an average molecular weight of about 12,500 and a polyoxypropylene fraction of about 30%; poloxamer 188 has an average molecular weight of about 8400 and a polyoxypropylene fraction of about 20%; poloxamer 338 has an average molecular weight of about 14,600 and a polyoxypropylene fraction of about 20 %; poloxamine 1107 has an average molecular weight of about 14,000, poloxamine 1307 has an average molecular weight of about 18,000. Polymers of this type are also referred to as reversibly gelling because their viscosity increases and decreases with an increase and decrease in temperature, respectively.
  • Such reversibly gelling systems are useful wherever it is desirable to handle a material in a fluid state, but performance is preferably in a gelled or more viscous state.
  • certain poly(ethyleneoxide)/poly(propyleneoxide) block copolymers have these properties; they are available commercially as Pluronic® poloxamers and Tetronic® poloxamines (BASF, Ludwigshafen, Germany) and generically known as poloxamers and poloxamines, respectively. See U.S. Pat. Nos. 4,188,373, 4,478,822 and 4,474,751; all of which are hereby incorporated by reference.
  • the average molecular weights of commercially available poloxamers and poloxamines range from about 1,000 to greater than 16,000 Daltons. Because the poloxamers are products of a sequential series of reactions, the molecular weights of the individual poloxamer molecules form a statistical distribution about the average molecular weight.
  • commercially available poloxamers contain substantial amounts of poly(oxyethylene) homopolymer and poly(oxyethylene)/poly(oxypropylene diblock polymers. The relative amounts of these byproducts increase as the molecular weights of the component blocks of the poloxamer increase. Depending upon the manufacturer, these byproducts may constitute from about 15% to about 50% of the total mass of the commercial polymer.
  • the reverse thermosensitive polymers may be purified using a process for the fractionation of water-soluble polymers, comprising the steps of dissolving a known amount of the polymer in water, adding a soluble extraction salt to the polymer solution, maintaining the solution at a constant optimal temperature for a period of time adequate for two distinct phases to appear, and separating physically the phases. Additionally, the phase containing the polymer fraction of the preferred molecular weight may be diluted to the original volume with water, extraction salt may be added to achieve the original concentration, and the separation process repeated as needed until a polymer having a narrower molecular weight distribution than the starting material and optimal physical characteristics can be recovered.
  • a purified poloxamer or poloxamine has a polydispersity index from about 1.5 to about 1.0. m certain embodiments, a purified poloxamer or poloxamine has a polydispersity index from about 1.2 to about 1.0.
  • the aforementioned process consists of forming an aqueous two-phase system composed of the polymer and an appropriate salt in water.
  • a soluble salt can be added to a single phase polymer- water system to induce phase separation to yield a high salt, low polymer bottom phase, and a low salt, high polymer upper phase.
  • Lower molecular weight polymers partition preferentially into the high salt, low polymer phase.
  • Polymers that can be fractionated using this process include polyethers, glycols such as poly(ethylene glycol) and poly(ethylene oxide)s, polyoxyalkylene block copolymers such as poloxamers, poloxamines, and polyoxypropylene/ polyoxybutylene copolymers, and other polyols, such as polyvinyl alcohol.
  • the average molecular weight of these polymers may range from about 800 to greater than 100,000 Daltons. See U.S. Patent 6,761,824 (hereby incorporated by reference).
  • the aforementioned purification process inherently exploits the differences in size and polarity, and therefore solubility, among the poloxamer molecules, the poly(oxyethylene) homopolymer and the poly(oxyethylene)/poly(oxypropylene) diblock byproducts.
  • the polar fraction of the poloxamer which generally includes the lower molecular weight fraction and the byproducts, is removed allowing the higher molecular weight fraction of poloxamer to be recovered.
  • the larger molecular weight poloxamer recovered by this method has physical characteristics substantially different from the starting material or commercially available poloxamer including a higher average molecular weight, lower polydispersity and a higher viscosity in aqueous solution.
  • WO 92/16484 discloses the use of gel permeation chromatography to isolate a fraction of poloxamer 188 that exhibits beneficial biological effects, without causing potentially deleterious side effects.
  • the copolymer thus obtained had a polydispersity index of 1.07 or less, and was substantially saturated.
  • the potentially harmful side effects were shown to be associated with the low molecular weight, unsaturated portion of the polymer, while the medically beneficial effects resided in the uniform higher molecular weight material.
  • Other similarly improved copolymers were obtained by purifying either the polyoxypropylene center block during synthesis of the copolymer, or the copolymer product itself (e.g., U.S. Pat. No. 5,523,492 and U.S. Pat. No. 5,696,298; both of which are hereby incorporated by reference).
  • a supercritical fluid extraction technique has been used to fractionate a polyoxyalkylene block copolymer as disclosed in U.S. Pat. No. 5,567,859 (hereby incorporated by reference).
  • a purified fraction was obtained, which was composed of a fairly uniform polyoxyalkylene block copolymer having a polydispersity of less than 1.17.
  • the lower molecular weight fraction was removed in a stream of carbon dioxide maintained at a pressure of 2200 pounds per square inch (psi) and a temperature of 40 0 C.
  • U.S. Pat. No. 5,800,711 discloses a process for the fractionation of polyoxyalkylene block copolymers by the batchwise removal of low molecular weight species using a salt extraction and liquid phase separation technique. Poloxamer 407 and poloxamer 188 were fractionated by this method. In each case, a copolymer fraction was obtained which had a higher average molecular weight and a lower polydispersity index as compared to the starting material. However, the changes in polydispersity index were modest and analysis by gel permeation chromatography indicated that some low-molecular-weight material remained.
  • the viscosity of aqueous solutions of the fractionated polymers was significantly greater than the viscosity of the commercially available polymers at temperatures between 10 0 C and 37 0 C, an important property for some medical and drug delivery applications. Nevertheless, some of the low molecular weight contaminants of these polymers are thought to cause deleterious side effects when used inside the body, making it especially important that they be removed in the fractionation process. As a consequence, polyoxyalkylene block copolymers fractionated by this process are not appropriate for all medical uses.
  • this polymer was developed for a different purpose, namely hemostasis in smaller and cooler surface-exposed arteries, and for certain embodiments may be too low for injection into a solid organ as the injection force needed during the initial animal experiments was rather great (results not shown). Therefore, for certain embodiments, such as for use in intraparenchymal temporary hemostasis as applied to the kidney at normal body temperatures, the ideal reverse thermosensitive polymer may be different.
  • a polymer with a higher transition temperature may be preferable.
  • a polymer with a transition temperature of about 30 0 C is preferred.
  • Modification of the transition temperature of a reverse thermosensitive polymer can be obtained in a number of ways.
  • the transition temperature can be modified either through the addition of transition temperature modifying additive or through the development of a modified polymer.
  • the transition temperature can be influenced by a number of additives, e.g., the addition of pharmaceutical fatty acid excipients such as sodium oleate, sodium laurate or sodium caprate.
  • solvents such as water, alcohols, especially Cj-C 5 alcohols such as ethanol, n- propanol, 2-propanol, isopropanol, t-butyl alcohol; ethers such as MTBE; ketones such as acetone, methyl ethyl ketone; humectants such as glycerol; glycols such as ethylene glycol, propylene glycol; emulsifiers such as lower, optionally polyhydric C 1 -C 5 alcohols partially esterified with long-chain (Ci 2 -C 24 ) fatty acids such as glycerol monostearate, isopropyl myristate, fatty acid ester of sugar alcohols such as sorbitan mono-fatty acid ester, polyethoxylated derivatives of such compounds, polyethoxyethylene fatty acid ester and fatty alcohol ether, cholesterol, cetyl stearyl alcohol, wool wax alcohols and synthetic surfactants
  • a contrast-enhancing agent can be added to the transient gel.
  • contrast-enhancing agents are radiopaque materials, paramagnetic materials, heavy atoms, transition metals, lanthanides, actinides, dyes, and radionuclide-containing materials.
  • compositions used in the methods of the invention have physico-chemical characteristics that make them suitable delivery vehicles for conventional small-molecule drugs, as well as macromolecular (e.g., peptides) drugs or other therapeutic products. Therefore, the composition comprising the thermosensitive polymer may further comprise a pharmaceutic agent selected to provide a pre-selected pharmaceutic effect.
  • a pharmaceutic effect is one which seeks to prevent or treat the source or symptom of a disease or physical disorder.
  • Pharmaceutics include those products subject to regulation under the FDA pharmaceutic guidelines.
  • the compositions used in methods of the invention are capable of solubilizing and releasing bioactive materials. Solubilization is expected to occur as a result of dissolution in the bulk aqueous phase or by incorporation of the solute in micelles created by the hydrophobic domains of the poloxamer. Release of the drug would occur through diffusion or network erosion mechanisms.
  • compositions used in the methods of the invention may simultaneously be utilized to deliver a wide variety of pharmaceutics to a wound site.
  • an effective amount of pharmaceutically active agent(s), which imparts the desirable pharmaceutic effect is incorporated into the reversibly gelling composition used in the methods of the invention.
  • the selected agent is water soluble, which will readily lend itself to a homogeneous dispersion throughout the reversibly gelling composition.
  • the agent(s) is non-reactive with the composition.
  • the delivered bioactive material includes anesthetics, antimicrobial agents (antibacterial, antifungal, antiviral), antiinflammatory agents, diagnostic agents, and wound-healing agents.
  • thermo sensitive polymer may be any substance having biological activity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof.
  • therapeutic agents which may be administered via the methods of the invention include, without limitation: antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelmintics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta- blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system
  • Suitable pharmaceuticals for parenteral administration are well known as is exemplified by the Handbook on Injectable Drugs, 6th Edition, by Lawrence A. Trissel, American Society of Hospital Pharmacists, Bethesda, Md., 1990 (hereby incorporated by reference).
  • the pharmaceutically active compound may be any substance having biological activity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof.
  • protein is art-recognized and for purposes of this invention also encompasses peptides.
  • the proteins or peptides may be any biologically active protein or peptide, naturally occurring or synthetic.
  • proteins include antibodies, enzymes, growth hormone and growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, somatostatin and its analogues, gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing molecules.
  • gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, adrenocor
  • the pharmaceutical agents may be selected from insulin, antigens selected from the group consisting of MMR (mumps, measles and rubella) vaccine, typhoid vaccine, hepatitis A vaccine, hepatitis B vaccine, herpes simplex virus, bacterial toxoids, cholera toxin B-subunit, influenza vaccine virus, bordetela pertussis virus, vaccinia virus, adenovirus, canary pox, polio vaccine virus, Plasmodium falciparum, bacillus calmette geurin (BCG), klebsiella pneumoniae, HIV envelop glycoproteins and cytokins and other agents selected from the group consisting of bovine somatropine (sometimes referred to as BST), estrogens, androgens, insulin growth factors (sometimes referred to as IGF), interleukin I, interleukin II and cytokins. Three such cytokins are interferon- ⁇ , interferon- ⁇ and tuftsin.
  • Examples of bacterial toxoids that may be incorporated in the compositions used in the methods of the invention are tetanus, diphtheria, pseudomonas A, mycobaeterium tuberculosis. Examples of that may be incorporated in the compositions used in the occlusion methods of the invention are HIV envelope glycoproteins, e.g., gp 120 or gp 160, for AIDS vaccines. Examples of anti-ulcer H2 receptor antagonists that may be included are ranitidine, cimetidine and famotidine, and other anti-ulcer drags are omparazide, cesupride and misoprostol. An example of a hypoglycaemic agent is glizipide.
  • Classes of pharmaceutically active compounds which can be loaded into that may be incorporated in the compositions used in the occlusion methods of the invention include, but are not limited to, anti-AIDS substances, anti-cancer substances, antibiotics, immunosuppressants (e.g., cyclosporine) anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, antihistamines, lubricants tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, miotics and anti-cholinergics, anti-glaucoma compounds, anti-parasite and/or anti-protozoal compounds, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents such as NSAIDs, local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters, proteins, cell response
  • Exemplary pharmaceutical agents considered to be particularly suitable for incorporation in the compositions used in the methods of the invention include but are not limited to imidazoles, such as miconazole, econazole, terconazole, saperconazole, itraconazole, metronidazole, fluconazole, ketoconazole, and clotrimazole, luteinizing- hormone-releasing hormone (LHRH) and its analogues, nonoxynol-9, a GnRH agonist or antagonist, natural or synthetic progestrin, such as selected progesterone, 17- hydroxyprogeterone derivatives such as medroxyprogesterone acetate, and 19- nortestosterone analogues such as norethindrone, natural or synthetic estrogens, conjugated estrogens, estradiol, estropipate, and ethinyl estradiol, bisphosphonates including etidronate, alendronate, tiludronate, resedronate,
  • any of a number of antibiotics and antimicrobials may be included in the thermosensitive polymers used in the methods of the invention.
  • Antimicrobial drugs preferred for inclusion in compositions used in the occlusion methods of the invention include salts of lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, clindamycin, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole and amanfadine and the like.
  • non-steroidal anti-inflammatory agents may be incorporated in the compositions used in the occlusion methods of the invention, such as propionic acid derivatives, acetic acid, fenamic acid derivatives, biphenylcarboxylic acid derivatives, oxicams, including but not limited to aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carporfen, and bucloxic acid and the like.
  • NSAIDS non-steroidal anti-inflammatory agents
  • a delivery system may be used to facilitate and control injection of the reverse thermosensitive polymer composition. Ideally, the injection system would minimize the need for dissection of the artery prior to injection. Further, in constructing an optimal injection system it may be helpful to determine the thumb pressure required to inject the polymer in liquid form through various diameter needles while maintaining a flow rate of 0.5 mL per second.
  • a tensile testing apparatus e.g., Instron®
  • Instron® can be used measure the force needed and resulting rate of compression to depress the plunger.
  • a cannula that can be detected in a vessel using standard non-invasive systems in the operating room (e.g., a handheld ultrasound) will aid in verifying that the cannula is correctly placed in the renal artery.
  • the catheter may be a dilatation catheter.
  • the catheter is 3-10 French in size, and more preferably 3-6 French.
  • a catheter can be used to dispense one or more fluids other than, or in addition to, the polymer solution.
  • the catheter may be a multiple lumen catheter with one lumen for the delivery of the polymer solution, other lumen for the delivery of other fluids such as a contrast agent solution.
  • the syringe or other mechanism may be used to inject the polymer solution into the body can be, for example, a 1-100 cc syringe, a 1-50 cc syringe or a 1-5 cc. Pressure applied to the syringe can be applied by hand or by an automated syringe pusher.
  • a system to provide auxiliary power to a syringe for injection of a viscous material e.g., a spring loaded plunger assisted device may be used.
  • Kits This invention also provides kits for conveniently and effectively implementing the methods of this invention.
  • kits comprise any of the polymers of the present invention or a combination thereof, and a means for facilitating their use consistent with methods of this invention.
  • Such kits may also included ice, a cold pack, or other means of cooling.
  • Such kits provide a convenient and effective means for assuring that the methods are practiced in an effective manner.
  • the compliance means of such kits includes any means which facilitates practicing a method of this invention.
  • Such compliance means include instructions, packaging, and dispensing means, and combinations thereof.
  • Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods.
  • this invention contemplates a kit including block copolymers of the present invention, and optionally instructions for their use.
  • the reverse thermosensitive copolymers of such a kit of the present invention are contained in one or more syringes.
  • Transient Gels of the Invention One aspect of the invention relates to a transient gel.
  • the present invention relates to the aforementioned transient gel and any of the attendant limitations, wherein the transient gel is a gel at mammalian physiological temperature.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises at least one optionally purified reverse thermosensitive polymer. In certain embodiments, the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises about 5% to about 35% of said reverse thermosensitive polymer. In certain embodiments, the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises about 10% to about 30% of said reverse thermosensitive polymer.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer has a polydispersity index from about 1.5 to about 1.0.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer has a polydispersity index from about 1.2 to about 1.0.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of block copolymers, random copolymers, graft polymers, and branched copolymers.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is a polyoxyalkylene block copolymer.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of poloxamer 407, poloxamer 288, poloxamer 188, poloxamer 338, poloxamer 118, Tetronic® 1107 or Tetronic® 1307.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is poloxamer 407.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of purified poloxamers and purified poloxamines.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of purified poloxamer 407, purified poloxamer 288, purified poloxamer 188, purified poloxamer 338, purified poloxamer 118, purified Tetronic® 1107 or purified Tetronic® 1307.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is purified poloxamer 407.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises an excipient.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises a pharmaceutical fatty acid excipient.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said pharmaceutical fatty acid excipient is sodium oleate, sodium laurate or sodium caprate.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises a therapeutic agent.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the therapeutic agent is selected from the group consisting of antiinflammatories, antibiotics, antimicrobials, chemotherapeutics, antivirals, analgesics, and antiproliferatives.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the therapeutic agent is an antibiotic.
  • the present invention relates to the aforementioned method, wherein said transient gel comprises a contrast-enhancing agent.
  • said contrast-enhancing agent is selected from the group consisting of radiopaque materials, paramagnetic materials, heavy atoms, transition metals, lanthanides, actinides, dyes, and radionuclide-containing materials.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel has a transition temperature of between about 20 0 C and about 50 0 C.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel has a transition temperature of between about 30 0 C and about 40 0 C.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature. In certain embodiments, the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; and said transient gel has a transition temperature of between about 20 0 C and about 50 °C.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; and said transient gel has a transition temperature of between about 30 °C and about 40 0 C.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; said transient gel has a transition temperature of between about 20 0 C and about 50 0 C; and said transient gel comprises at least one optionally purified reverse thermosensitive polymer selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; said transient gel has a transition temperature of between about 30 0 C and about 40 0 C; and said transient gel comprises at least one optionally purified reverse thermosensitive polymer selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises an anionic, cationic, or non-ionically crosslinkable polymer.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan, potassium gellan, carboxy methyl cellulose, hyaluronic acid and polyvinyl alcohol.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises phosphate, citrate, borate, succinate, maleate, adipate, oxalate, calcium, magnesium, barium, strontium, or a combination thereof.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan and potassium gellan; and further comprises calcium, magnesium or barium.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate or potassium alginate; and further comprises composition comprises calcium.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of sodium gellan and potassium gellan; and further comprises magnesium.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises hyaluronic acid; and further comprises calcium. In certain embodiments, the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises polyvinyl alcohol; and further comprises borate.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises proteins selected from the group consisting of collagen, gelatin, elastin, albumin, protamine, fibrin, fibrinogen, keratin, reelin, caseine, and mixture thereof.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises hyaluronic acid, chitosan, or a mixture thereof.
  • the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises synthetic materials selected from the group consisting of alginate, pectin, methylcellulose, carboxymethylcellulose, and mixtures thereof. In certain embodiments, the present invention relates to any one of the aforementioned transient gels and any of the attendant limitations, wherein said transient gel comprises crosslinkable polymers.
  • One aspect of the invention relates to a method of perfusive organ hemostasis in a subject, comprising the step of introducing into an arterial vessel in fluid communication with an organ a volume of a composition, wherein said volume is sufficient to perfuse substantially said organ; and said composition forms a transient gel in said organ.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the volume of said composition is about 1-25 mL or about 1-10 mL.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is introduced over about 1-30 seconds or about 2-20 seconds.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel is a gel at mammalian physiological temperature. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises at least one optionally purified reverse thermosensitive polymer.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises about 5% to about 35% of said reverse thermosensitive polymer.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises about 10% to about 30% of said reverse thermosensitive polymer. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer has a polydispersity index from about 1.5 to about 1.0.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer has a polydispersity index from about 1.2 to about 1.0.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of block copolymers, random copolymers, graft polymers, and branched copolymers.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is a polyoxyalkylene block copolymer. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of poloxamer 407, poloxamer 288, poloxamer 188, poloxamer 338, poloxamer 118, Tetronic® 1107 and Tetronic® 1307.
  • said at least one optionally purified reverse thermosensitive polymer is poloxamer 407.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of purified poloxamers and purified poloxamines.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of purified poloxamer 407, purified poloxamer 288, purified poloxamer 188, purified poloxamer 338, purified poloxamer 118, purified Tetronic® 1107 and purified Tetronic® 1307.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is purified poloxamer 407.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises an excipient. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a pharmaceutical fatty acid excipient.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said pharmaceutical fatty acid excipient is sodium oleate, sodium laurate or sodium caprate.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a therapeutic agent.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the therapeutic agent is selected from the group consisting of antiinflammatories, antibiotics, antimicrobials, chemotherapeutics, antivirals, analgesics, and antiproliferatives. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the therapeutic agent is an antibiotic.
  • the present invention relates to the aforementioned method, wherein said transient gel comprises a contrast-enhancing agent.
  • the present invention relates to the aforementioned method, wherein said contrast-enhancing agent is selected from the group consisting of radiopaque materials, paramagnetic materials, heavy atoms, transition metals, lanthanides, actinides, dyes, and radionuclide-containing materials.
  • said transient gel has a transition temperature of between about 20 0 C and about 50 0 C.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel has a transition temperature of between about 30 0 C and about 40 0 C.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; and said transient gel has a transition temperature of between about 20 °C and about 50 0 C.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; and said transient gel has a transition temperature of between about 30 °C and about 40 0 C. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; said transient gel has a transition temperature of between about 20 0 C and about 50 0 C; and said transient gel comprises at least one optionally purified reverse thermosensitive polymer selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the volume of said transient gel at physiological temperature is about 80% to about 120% of its volume below its transition temperature; said transient gel has a transition temperature of between about 30 0 C and about 40 0 C; and said transient gel comprises at least one optionally purified reverse thermosensitive polymer selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises an anionic, cationic, or non-ionically crosslinkable polymer.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan, potassium gellan, carboxy methyl cellulose, hyaluronic acid and polyvinyl alcohol.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises phosphate, citrate, borate, succinate, maleate, adipate, oxalate, calcium, magnesium, barium, or strontium.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan and potassium gellan; and calcium, magnesium or barium.
  • said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan and potassium gellan; and calcium, magnesium or barium.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of alginic acid, sodium alginate and potassium alginate; and calcium.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a polymer selected from the group consisting of sodium gellan and potassium gellan; and magnesium.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises hyaluronic acid; and calcium.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises polyvinyl alcohol; and borate.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a protein selected from the group consisting of collagen, gelatin, elastin, albumin, protamine, fibrin, fibrinogen, keratin, reelin, and caseine.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises hyaluronic acid, or chitosan.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises alginate, pectin, methylcellulose, or carboxymethylcellulose.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said transient gel comprises a crosslinkable polymer.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said organ is a highly vascularized organ. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said organ is a kidney, a liver, a prostate, a brain, a uterus, or a spleen.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said organ is a kidney, a liver or a prostate.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said organ is a kidney. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the lifetime of said transient gel is about twenty minutes.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the lifetime of said transient gel is about thirty minutes.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the lifetime of said transient gel is about forty minutes. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said subject is a mammal.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said subject is a human.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is introduced using a syringe, cannula, catheter or percutaneous access device.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is introduced using a dual lumen catheter or a triple lumen catheter.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the catheter is 3-10 French or 3-6 French in size.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the catheter can be used to dispense one or more fluids other than, or in addition to, the polymer solution.
  • the catheter may be a multiple lumen catheter with one lumen for the delivery of the polymer solution, other lumen for the delivery of other fluids such as a contrast agent solution.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is introduced using a syringe.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein the syringe used to inject the polymer solution into the body can be a 1-100 cc syringe, a 1-50 cc syringe or a 1-5 cc syringe. Pressure applied to the syringe can be applied by hand or by an automated syringe pusher.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is cooled to about 15 0 C prior to introduction.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is cooled to about 10 0 C prior to introduction.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is cooled to about 5 0 C prior to introduction. In certain embodiments, the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is cooled to about 0 0 C prior to introduction.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, wherein said composition is cooled with ice, water, or a cold pack prior to introduction.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, further comprising introducing saline to aid in the disolution of said transient gel.
  • the present invention relates to any one of the aforementioned methods and any of the attendant limitations, further comprising the step of cooling said organ.
  • kits of the Inventions relate to a kit for perfusive organ hemostasis, comprising instructions for use thereof; and a first container comprising a volume of a composition, wherein said composition forms a transient gel at mammalian physiological temperature.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, further comprising a cold pack. In certain embodiments, the present invention relates to the aforementioned kit and any of the attendant limitations, further comprising a syringe or cannula.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises at least one optionally purified reverse thermosensitive polymer.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises about 5% to about 35% of said reverse thermosensitive polymer.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises about 10% to about 30% of said reverse thermosensitive polymer.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer has a polydispersity index from about 1.5 to about 1.0. In certain embodiments, the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer has a polydispersity index from about 1.2 to about 1.0.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of block copolymers, random copolymers, graft polymers, and branched copolymers.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is a polyoxyalkylene block copolymer.
  • said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of poloxamer 407, poloxamer 288, poloxamer 188, poloxamer 338, poloxamer 118, Tetronic® 1107 and Tetronic® 1307.
  • said at least one optionally purified reverse thermosensitive polymer is poloxamer 407.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of purified poloxamers and purified poloxamines.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is selected from the group consisting of purified poloxamer 407, purified poloxamer 288, purified poloxamer 188, purified poloxamer 338, purified poloxamer 118, purified Tetronic® 1107 and purified Tetronic® 1307.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said at least one optionally purified reverse thermosensitive polymer is purified poloxamer 407.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises an excipient.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a pharmaceutical fatty acid excipient.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said pharmaceutical fatty acid excipient is sodium oleate, sodium laurate or sodium caprate.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a therapeutic agent.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the therapeutic agent is selected from the group consisting of antiinflammatories, antibiotics, antimicrobials, chemotherapeutics, antivirals, analgesics, and antiproliferatives.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the therapeutic agent is an antibiotic.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a contrast-enhancing agent.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said contrast-enhancing agent is selected from the group consisting of radiopaque materials, paramagnetic materials, heavy atoms, transition metals, lanthanides, actinides, dyes, and radionuclide-containing materials.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition has a transition temperature of between about 20 0 C and about 50 0 C.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition has a transition temperature of between about 30 °C and about 40 °C.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the volume of said composition at physiological temperature is about 80% to about 120% of its volume below its transition temperature.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the volume of said composition at physiological temperature is about 80% to about 120% of its volume below its transition temperature; and said composition has a transition temperature of between about 20 °C and about 50 0 C.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the volume of said composition at physiological temperature is about 80% to about 120% of its volume below its transition temperature; and said composition has a transition temperature of between about 30 °C and about 40 °C.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the volume of said composition at physiological temperature is about 80% to about 120% of its volume below its transition temperature; said composition has a transition temperature of between about 20 0 C and about 50 °C; and said composition comprises at least one optionally purified reverse thermosensitive polymer selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein the volume of said composition at physiological temperature is about 80% to about 120% of its volume below its transition temperature; said composition has a transition temperature of between about 30 °C and about 40 °C; and said composition comprises at least one optionally purified reverse thermosensitive polymer selected from the group consisting of poloxamers and poloxamines.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises an anionic, cationic, or non-ionically crosslinkable polymer.
  • said composition comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan, potassium gellan, carboxy methyl cellulose, hyaluronic acid and polyvinyl alcohol.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises phosphate, citrate, borate, succinate, maleate, adipate, oxalate, calcium, magnesium, barium, or strontium.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a polymer selected from the group consisting of alginic acid, sodium alginate, potassium alginate, sodium gellan and potassium gellan; and calcium, magnesium or barium.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a polymer selected from the group consisting of alginic acid, sodium alginate or potassium alginate; and calcium.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a polymer selected from the group consisting of sodium gellan and potassium gellan; and magnesium.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises hyaluronic acid; and calcium.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises polyvinyl alcohol; and borate.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a protein selected from the group consisting of collagen, gelatin, elastin, albumin, protamine, fibrin, fibrinogen, keratin, reelin, and caseine.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises hyaluronic acid, or chitosan.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises alginate, pectin, methylcellulose, or carboxymethylcellulose.
  • the present invention relates to the aforementioned kit and any of the attendant limitations, wherein said composition comprises a crosslinkable polymer.
  • Example 1 Partial Nephrectomy. Partial nephrectomy with internal renal vascular occlusion using a reverse thermosensitive polymer solution was attempted in 2 pigs. After the pig was intubated and sedated a right flank incision was performed from the rib cage to just above the pubic symphysis. Full exposure of the right kidney, the renal vein, renal artery, aorta and vena cava was obtained via a retroperitoneal approach. The aorta was canulated retrograde from the right iliac artery with the catheter tip lying about 15 mm proximal to the origin of the right renal artery.
  • Example 2 Renal Exposure.
  • a study of renal exposure was similar to the above procedure. A catheter was inserted directly into the renal artery. A slow injection of 1.5 ml of the polymer produced ischemia identical to that described above. A heminephrectomy was performed in this case.
  • Example 3 Sample Purification. Poloxamer 407 (486.0 g, lot number WPHT- 543B), purchased from BASF Corporation, Mount Olive, NJ., was dissolved in deionized water (15,733 g). The solution was maintained at 0.1°C and 2335.1 g of (NH 4 ) 2 SO 4 were added. The solution was equilibrated at 2 0 C and after two distinct phases formed, the lower phase was discarded, and the upper phase (2060 g) was collected and weighed. Deionized water (14159 g) was added and the solution was equilibrated to 2°C. Next, 2171.6 g of (NH 4 ) 2 SO 4 were added with stirring.
  • the solution was maintained at approximately 2°C until two phases formed.
  • the upper phase (3340 g) was isolated and diluted with 12879 g of deionized water. The solution was chilled to about 2.2°C and 2062 g of (NBU) 2 SO 4 were added. The phases were allowed to separate as above.
  • the upper phase was isolated and extracted with 4 liters of dichloromethane. Two phases were allowed to form overnight.
  • the organic (lower) phase was isolated and approximately 2 kg of sodium sulfate (Na 2 SO 4 ) were added to it to remove the remaining water.
  • the dichloromethane phase was filtered through a PTFE filter (0.45 ⁇ m pore size) to remove the undissolved salts.
  • Example 4 Sample In- Vitro Viscosity Testing. Viscosity changes can be measured in a Brookfield Cone and Cup viscometer with temperature control.
  • a graph of the viscosity changes of poloxamer 407 clearly shows polymer concentrations from approximately 12.5 w% until at least 20 w% will show steep increases in solution viscosities with temperature.
  • the onset of gelation is dependent on the temperature and higher polymer concentrations lead to earlier onsets of gelation.
  • polymer concentrations below approximately 12.5 w% do not demonstrate an increase in solution viscosity with temperature and remain liquid even at body temperature.
  • the polymer solution can be injected as a soft gel at a specific temperature (e.g., the temperature of a typical OR) into the arteriotomy and the rise in temperature leads to a stiff gel.
  • the gel will start to dissolve in blood and when the concentration of the polymer decreases, without any possibility of resolidifying into a gel at physiological temperatures.
  • cooling of the gel with ice or cold saline would liquefy the gel as the temperature falls below the gelation point. As a liquid, it quickly dilutes in blood and again there is no possibility for it to turn back into a gel at physiological temperatures.
  • Example 5 Gelation Temperature of Selected Pluronic® and Tetronic® Polymer
  • Example 6a Studies on Vertebrate Animals. Animal studies could further support the feasibility of using reverse thermosensitive polymers to achieve effective hemostasis during partial nephrectomy. This involves all aspects of the arterial and venous system of the kidney, as well as the detailed anatomy and physiology of the medulla, which can not be replicated in an in- vitro model. The anatomy of the omnivore swine is similar to that of the human, thereby creating the best simulation of conditions in a human operation, and the swine kidney is a classic model for human kidneys. M. M. Swindle, et al. , "Swine as models in experimental surgery," J Invest Surg. 1988, 1(1), 65-79.
  • Acute experiments using ordinary farm swine will be performed.
  • the pigs will weigh about 30 to 40 kg, slightly smaller than human size but sufficient to evaluate the feasibility of our hemostatic agent.
  • Each pig will undergo a partial nephrectomy.
  • the use of the transient gels of the invention to obtain temporary hemostasis will be evaluated.
  • the pig will be induced with an intramuscular mixture containing acepromazine (1.1 mg/kg) and atropine (0.05 mg/kg) as a pre-anesthetic. Five to fifteen minutes after pre- anesthetic administration the pig will be induced with ketamine (20 mg/kg) and xylazine (2.0 mg/kg) via IM injection. After the pig has reached a level of anesthesia to allow endotracheal intubation it will be intubated. Following intubation, the animal will be maintained throughout the preparation and surgery period on inhalation anesthesia (on a semiclosed circuit inhalation of isoflurane to effect). Assisted ventilation, if necessary, will be accomplished with a ventilator. An IV catheter will be aseptically placed in the ear vein or other appropriate vessel.
  • the pig Following induction of anesthesia, the pig will be prepared by shaving the skin, and brought to the operating room. The animal will be ventilated as above. A right paramedian incision from the costal margin to just above the inguinal ligament will be opened to the peritoneum by dividing the obligue abdominal muscles about one inch lateral to their rectus insertion. The peritoneum will be reflected from the kidney, exposing the vena cava and the aorta. The kidney, renal artery and renal vein will be cleaned and exposed. A thermister will be place in the aorta just proximal to the renal artery for monitoring temperature of the blood at the time of injection.
  • a 25 gague catheter will be introduced to the renal artery by puncture, and advanced 1.5 cm distally. It will remain in place for the duration of the experiment. Approximately 1-2 cc of the polymer will be injected. The volume and rate of injection will be determined prior to surgery based, in part, on viscosity measurements and polymerization temperature information. Data regarding each injection will include: injection time, rate of injection, volume of injection, blood temperature, time to cessation of blood flow, completeness of blood flow cessation, time to perform partial nephrectomy, including plication of the severed renal surface, and time to return of blood flow. These data will be correlated to the physical properties of the polymer.
  • the animal will be maintained until there is complete return of blood flow and normal appearance of the kidney. It will then be kept in stable condition for one additional hour, to ensure complete reperfusion of the remaining renal mass. The animal will then be euthanized with an overdose of pentobarbital and phenytoin. The resected renal portion and the re-perfused renal portion will be sent for microscopic analysis. The remaining pig carcass will be disposed of. Euthanasia will be achieved with an intravenous injection of pentobarbital sodium and phenytoin as follows: Drugs: pentobarbital sodium and phenytoin sodium; Dose: 1 cc/10 pounds; and Route: rapid intravenous injection.
  • Example 6b Sample procedure for pig anesthesia. The following are sample protocols which can be followed in performing the procedures described in Example 6a.
  • Animal Identification Each animal will be identified by a tattoo in the pinna of the ear or an ear tag.
  • Anesthesia; option #1 The pig will be induced with an intramuscular cocktail containing Telazol (4.4 mg/kg), Xylazine (2.2 mg/kg) and Atropine (0.05 mg/kg) to a level of anesthesia to allow endotracheal intubation. Following intubation, the animal will be maintained throughout the preparation and surgery period on inhalation anesthesia (on a semi-closed circuit inhalation of isoflurane to effect). Assisted ventilation, if necessary, will be accomplished with a ventilator. An IV catheter will be aseptically placed in the ear vein or other appropriate vessel.
  • Surgical Preparation Sterile procedures will be followed in the event of survival surgery. Depilitation of the surgical site will be accomplished with an electric animal clipper equipped with a surgical shaving blade. The area will be vacuumed to remove all clippings and debris, then scrubbed in an alternating sequence with an aqueous iodophor solution of 1% available iodine and 70% isopropyl alcohol a minimum of three times. Following drying, the entire area will be painted with a solution of 0.7% available iodine and 74% isopropyl alcohol. The anesthetized and surgically prepared animal will be delivered to the operating table and placed in the desired recumbent position. A sterile surgical drape will be placed over the entire animal and surgical table. Intravenous fluid therapy will be administered at the maintenance rate of 4-6 ml/kg/hr.
  • Temperature, pulse and respiratory rate will be monitored postoperatively as directed by the veterinary staff and/or primary investigator. The animal will be observed daily postoperatively to determine health status on the basis of food consumption, excretion and general attitude. All animals will also be observed daily for the presence of pain and/or discomfort and analgesics administered as necessary.
  • Analgesics During the first 48 hrs. postoperative period, buprenex (0.01-0.02 mg/kg/IM Q 12hr) will be administered. Following the first 48hr. period, analgesics will be administered as necessary.
  • Euthanasia will be achieved with an intravenous injection of pentobarbital sodium and phenytoin sodium as directed by the label instructions on the bottle. If the animal is in a deep plane of anesthesia, a saturated solution of potassium chloride may be administered intravenous to accomplish euthanasia. The potassium ion is cardiotoxic, and rapid intravenous or intracardiac administration of 1-2 mmol/kg of body weight will cause cardiac arrest. Following administration of the drug, the animal will be examined to ensure that respiratory function has ceased and there is no palpable cardiac function. Incorporation by Reference

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009086206A3 (en) * 2007-12-20 2010-04-01 Tautona Group, L.P. Compositions and methods for joining non-conjoined lumens
WO2010091154A3 (en) * 2009-02-06 2010-12-23 Tautona Group, L.P. Compositions and methods for joining non-conjoined lumens
US8197499B2 (en) 2006-06-21 2012-06-12 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for joining non-conjoined lumens
CN102548538A (zh) * 2009-09-22 2012-07-04 V生命科学技术有限公司 治疗糖尿病足溃疡的局部制剂
US8216259B2 (en) 2006-06-21 2012-07-10 The Board Of Trustees Of The Leland Stanford Jr. University Compositions and methods for joining non-conjoined lumens
US8608760B2 (en) 2006-06-21 2013-12-17 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for joining non-conjoined lumens
EP2490722A4 (en) * 2009-10-21 2014-03-05 Otonomy Inc MODULATION OF THE TEMPERATURE OF GELIFICATION OF FORMULATIONS CONTAINING POLOXAMERS
US8828980B2 (en) 2008-05-14 2014-09-09 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US9017664B2 (en) 2006-12-15 2015-04-28 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US9233068B2 (en) 2008-07-21 2016-01-12 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of OTIC disorders
US9433699B2 (en) 2011-11-21 2016-09-06 Innotherapy Inc. Hydrogel comprising catechol group-coupled chitosan or polyamine and poloxamer comprising thiol group coupled to end thereof, preparation method thereof, and hemostat using same
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2866133B2 (ja) 1989-07-25 1999-03-08 株式会社リコー 液体噴射記録装置及び方法
JP2989243B2 (ja) 1990-10-16 1999-12-13 株式会社リコー 液体噴射記録方法及び装置
JP2989242B2 (ja) 1990-10-16 1999-12-13 株式会社リコー 液体噴射記録方法及び装置
JP2957676B2 (ja) 1990-10-16 1999-10-06 株式会社リコー 液体噴射記録装置及び方法
WO2008018892A2 (en) * 2005-12-22 2008-02-14 Pluromed, Inc. Methods and kits for treating lacerations and puncture wounds using inverse thermosensitive polymers
US20080208163A1 (en) * 2007-02-22 2008-08-28 Pluromed, Inc. Use of Reverse Thermosensitive Polymers to Control Biological Fluid Flow Following a Medical Procedure
US8394795B2 (en) * 2008-02-29 2013-03-12 Array Biopharma Inc. Pyrazole [3, 4-B] pyridine Raf inhibitors
CN106037857A (zh) * 2008-02-29 2016-10-26 普拉罗美德公司 通过加热热敏聚合物进行的局部栓塞
US9060749B2 (en) 2011-08-12 2015-06-23 Boston Scientific Scimed, Inc. Methods, compositions and kits for performing anastomosis procedures in conjunction with a radical prostatectomy procedure
DE102013211316A1 (de) * 2013-06-17 2014-12-18 Aesculap Ag Hämostyptikum
ITMI20131924A1 (it) * 2013-11-20 2015-05-21 Cosmo Technologies Ltd Emulsions or microemulsions for use in endoscopic mucosal resectioning and/or endoscopic submucosal dissection emulsioni o microemulsioni per uso nella resezione mucosale endoscopica e/o dissezione submucosale endoscopica
ITMI20131927A1 (it) * 2013-11-20 2015-05-21 Cosmo Technologies Ltd Emulsions or microemulsions for use in endoscopic mucosal resectioning and/or endoscopic submucosal dissection. emulsioni o microemulsioni per uso nella resezione mucosale endoscopica e/o dissezione submucosale endoscopica
JP6562902B2 (ja) * 2014-03-28 2019-08-21 テルモ株式会社 生体血管内血液置換用液体、生体血管内血液置換用液体製剤およびプレフィルドシリンジ
AR102147A1 (es) * 2014-10-01 2017-02-08 Als Mountain Llc Composición farmacéutica que comprende aspirina, metformina y serotonina con agente tensioactivo no iónico
US20170274189A1 (en) * 2016-03-24 2017-09-28 Ethicon, Inc. Single lumen balloon delivery catheter with lumen bypass at balloon
CN108714243A (zh) * 2017-06-08 2018-10-30 重庆大学 用于脑出血术后止血的植入剂及其制备方法
WO2019163012A1 (ja) * 2018-02-21 2019-08-29 国立大学法人信州大学 液体塞栓剤組成物
EP4233914A3 (en) 2018-03-16 2023-10-18 Critical Innovations, LLC Systems and methods relating to medical applications of synthetic polymer formulations
CN112138204A (zh) * 2019-06-26 2020-12-29 广东博与再生医学有限公司 骨止血材料
JP7546265B2 (ja) * 2020-05-22 2024-09-06 ウェトラブホールディング株式会社 生体組織用二液型バインダーおよび生体組織用二液型充填材
CN111632189B (zh) * 2020-05-27 2021-12-14 深圳先进技术研究院 基于海洋源明胶的可注射水凝胶止血剂及应用和应用方法
US12410293B2 (en) 2022-11-07 2025-09-09 Critical Innovations Llc Systems and methods relating to medical applications of inverse thermosensitive polymer foam formulations

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3889685A (en) * 1973-11-02 1975-06-17 Cutter Lab Tubular unit with vessel engaging cuff structure
US4188373A (en) * 1976-02-26 1980-02-12 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
US4168708A (en) * 1977-04-20 1979-09-25 Medical Engineering Corp. Blood vessel occlusion means suitable for use in anastomosis
US4474751A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Ophthalmic drug delivery system utilizing thermosetting gels
US4478822A (en) * 1983-05-16 1984-10-23 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
US5567859A (en) * 1991-03-19 1996-10-22 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5843156A (en) * 1988-08-24 1998-12-01 Endoluminal Therapeutics, Inc. Local polymeric gel cellular therapy
US4946463A (en) * 1989-04-10 1990-08-07 Pioneering Technologies, Inc. Vessel occluder
ATE130517T1 (de) * 1990-08-08 1995-12-15 Takeda Chemical Industries Ltd Intravaskulär embolisierendes mittel mit gehalt an einem die angiogenesis hemmenden stoff.
CN1069741A (zh) * 1991-03-19 1993-03-10 西特克斯公司 具有改进的生物活性的聚氧丙烯/聚氧乙烯共聚物
US5696298A (en) * 1991-03-19 1997-12-09 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5939485A (en) * 1995-06-19 1999-08-17 Medlogic Global Corporation Responsive polymer networks and methods of their use
US5800711A (en) * 1996-10-18 1998-09-01 Mdv Technologies, Inc. Process for the fractionation of polyoxyalkylene block copolymers
US6120751A (en) * 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US7485317B1 (en) * 1999-02-05 2009-02-03 The Regents Of The University Of California Thermo-reversible polymer for intralumenal implant
CN101708165A (zh) * 2000-03-24 2010-05-19 生物领域医疗公司 用于主动栓塞术的微球体
US6761824B2 (en) * 2000-08-17 2004-07-13 Reeve Lorraine E Process for the fractionation of polymers
US7838699B2 (en) * 2002-05-08 2010-11-23 Biosphere Medical Embolization using degradable crosslinked hydrogels
JP4909071B2 (ja) * 2003-03-24 2012-04-04 プルーローメッド， インコーポレイテッド 逆感熱性ポリマーを使用する一時的な塞栓形成
JP4898447B2 (ja) * 2003-10-14 2012-03-14 プルーロームド インコーポレイテッド 結石破砕術の際の腎結石破片の閉じ込め
US7700086B2 (en) * 2003-11-06 2010-04-20 Pluromed, Inc. Internal clamp for surgical procedures
US20060253099A1 (en) * 2005-04-21 2006-11-09 Medtronic Vascular, Inc. Guiding catheter with resiliently compressible occluder
PT2601972E (pt) * 2005-05-02 2015-02-09 Gen Hospital Corp Tratamento de litíase renal sem litotripsia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP2094169A4 *

Cited By (27)

* Cited by examiner, † Cited by third party
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US8197499B2 (en) 2006-06-21 2012-06-12 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for joining non-conjoined lumens
US8216259B2 (en) 2006-06-21 2012-07-10 The Board Of Trustees Of The Leland Stanford Jr. University Compositions and methods for joining non-conjoined lumens
US8608760B2 (en) 2006-06-21 2013-12-17 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for joining non-conjoined lumens
US9017664B2 (en) 2006-12-15 2015-04-28 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
US9655988B2 (en) 2006-12-15 2017-05-23 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US9636433B2 (en) 2006-12-15 2017-05-02 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US8172861B2 (en) 2007-12-20 2012-05-08 Tautona Group, L.P. Compositions and methods for joining non-conjoined lumens
WO2009086206A3 (en) * 2007-12-20 2010-04-01 Tautona Group, L.P. Compositions and methods for joining non-conjoined lumens
US9511020B2 (en) 2008-05-14 2016-12-06 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8828980B2 (en) 2008-05-14 2014-09-09 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US9744126B2 (en) 2008-05-14 2017-08-29 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
US9603796B2 (en) 2008-07-21 2017-03-28 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US11369566B2 (en) 2008-07-21 2022-06-28 Alk-Abelló, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9867778B2 (en) 2008-07-21 2018-01-16 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9233068B2 (en) 2008-07-21 2016-01-12 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of OTIC disorders
WO2010091154A3 (en) * 2009-02-06 2010-12-23 Tautona Group, L.P. Compositions and methods for joining non-conjoined lumens
US8563037B2 (en) 2009-02-06 2013-10-22 Tautona Group, L.P. Compositions and methods for joining non-conjoined lumens
CN102548538A (zh) * 2009-09-22 2012-07-04 V生命科学技术有限公司 治疗糖尿病足溃疡的局部制剂
CN102548538B (zh) * 2009-09-22 2014-03-12 V生命科学技术有限公司 治疗糖尿病足溃疡的局部制剂
EP2490722A4 (en) * 2009-10-21 2014-03-05 Otonomy Inc MODULATION OF THE TEMPERATURE OF GELIFICATION OF FORMULATIONS CONTAINING POLOXAMERS
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US10202585B2 (en) 2009-12-22 2019-02-12 Lifebond Ltd Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US9433699B2 (en) 2011-11-21 2016-09-06 Innotherapy Inc. Hydrogel comprising catechol group-coupled chitosan or polyamine and poloxamer comprising thiol group coupled to end thereof, preparation method thereof, and hemostat using same
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices

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