DEVICE AND METHOD FOR REVERSIBLE OCCLUSION OF BODY LUMENS

Abstract

The technology disclosed herein generally concerns a system and method for reversibly occluding a body lumen.

Claims

1. A stimulus-responsive occlusion device for occlusion a body lumen in vivo, the device exhibiting a solid or semi-solid state at a physiological temperature and a liquified state at a temperature lower than the physiological temperature, the occlusion device is or comprising at least one reverse thermo-responsive (RTR) polymer or a water-formulation comprising a thermo-responsive polymer.

2. The device according to claim 1, wherein the RTR polymer comprises chain extended poly(ethylene oxide); chain extended poly(propylene oxide); di-blocks of poly(ethylene oxide) and poly(propylene oxide); triblocks of poly(ethylene oxide) and poly(propylene oxide); or mixtures thereof.

3. The device according to claim 1, wherein the RTR polymer comprises poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblocks; random or alternating reverse thermo-responsive PEO-PPO block copolymers; N-alkyl substituted acrylamides; poly(ethylene oxide)-polylactic acid copolymers; poly(ethylene oxide)-polycaprolactone copolymers; and/or amphiphilic polymers.

4. The device according to claim 3, wherein the RTR polymer comprises poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) triblock.

5. The device according to claim 4, wherein the RTR polymer having a structure -[E-(BCB)]n, wherein B is polyethylene oxide (PEO), C is polypropylene oxide (PPO), n is an integer designating the number of blocks in the polymer and being 2 or more, and E is a chain extender moiety connecting the triblocks to each other.

6. The device according to claim 5, wherein E is derived from a bifunctional material selected di-isocyanates, di-acyl chlorides, di-carboxylic acids and di-anhydrides.

7. The device according to claim 5, wherein E is derived from a di-isocyanate.

8. The device according to claim 7, wherein E comprises a urethane moiety.

9. The device according to claim 7, wherein the di-isocyanate is selected from the group consisting of hexamethylene di-isocyanate (HDI), methylene di-phenyl di-isocyanate (MDI), isophorone diisocyanate, lysine diisocyanate ethyl ester and toluene di-isocyanate.

10. The device according to claim 9, wherein the di-isocyanate is HDI.

11. The device according to claim 1, comprising one or more additional materials or solid components, optionally being a drug or an active material, selected from the group consisting of drugs and drug residues, oligopeptide sequences, growth factors, hormones, materials containing genetic information, cells, contraceptive agents, ion eluting agents, metals or metallic materials, anti-restenosis agents, antibacterial agents, antifungal agents, antimicrobial agents, and antibiotics.

12. The device according to claim 1, wherein the body lumen is fallopian tube or vas deferens.

13. A method of occluding a body lumen, the method comprising delivering at least one occlusion device to a region of the lumen to be occluded, the device is or comprising an occlusion material or a composition in a form of a reverse thermo-responsive (RTR) polymer having a solid or semi-solid state at a physiological temperature and a liquified or flowable state at a temperature below physiological temperature, wherein delivering is achievable at a temperature below the physiological temperature; and warming the occlusion material or composition to the physiological temperature or to a temperature above the physiological temperature to solidify the material, thereby occluding the region of the lumen.

14. The method according to claim 13, wherein the RTR polymer comprises poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) triblocks.

15. The method according to claim 13, wherein the RTR polymer is of a structure -[E-(BCB)]n, wherein B is polyethylene oxide (PEO), C is polypropylene oxide (PPO), n is an integer designating the number of blocks in the polymer and being 2 or more, and E is a chain extender connecting a triblock to another triblock.

16. The method according to claim 15, wherein E comprises a urethane moiety.

17. The method according to claim 13, wherein the body lumen is fallopian tube or vas deferens.

18. The method according to claim 13, wherein occlusion is for a period of several days to several years.

19. A method of clearing an occluded body lumen, wherein occlusion is provided by a solid or a semi-solid reverse thermo-responsive (RTR) polymer positioned in the body lumen and having a solid or semi-solid state at a physiological temperature and a liquified or flowable state at a temperature below physiological temperature, wherein the occlusion prevents flow or transfer of materials through the body lumen, the method comprising reducing a temperature at the occluded body lumen to a temperature below physiological temperature to thereby liquefy the RTR polymer, restoring flow of materials through the body lumen.

20. A method of temporarily occluding a body lumen selected from fallopian tube(s) and vas deferens, the method comprising delivering at least one occlusion device to a region of the lumen to be occluded, the device is or comprising an occlusion material or a composition in a form of a reverse thermo-responsive (RTR) polymer comprising chain extended poly(ethylene oxide); chain extended poly(propylene oxide); di-blocks of poly(ethylene oxide) and poly(propylene oxide); triblocks of poly(ethylene oxide) and poly(propylene oxide); or mixtures thereof, wherein the RTR polymer having a solid or semi-solid state at a physiological temperature and a liquified or flowable state at a temperature below physiological temperature, wherein delivering is achievable at a temperature below the physiological temperature; warming the occlusion material or composition to the physiological temperature or to a temperature above the physiological temperature to solidify the material, thereby occluding the region of the lumen; and at a time period following occlusion of the region of the lumen, clearing the region of the lumen by cooling the solidified material to a temperature below the physiological temperature to liquefying the solidified material.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0193] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the principles of the invention.

[0194] FIG. 1 presents a generic depiction of the PEO-PPO-PEO triblocks.

[0195] FIG. 2 presents the shortcomings of the PEO-PPO-PEO F127 triblock.

[0196] FIG. 3 depicts synthesis of the PF127 polyether urethane.

[0197] FIGS. 4A-B provide FTIR spectra of F127 (A) and PF127 (B).

[0198] FIG. 5 provides NMR spectra of the PF polyether urethane formed.

[0199] FIG. 6 provides DSC thermograms of F127 and PF127.

[0200] FIG. 7 provides viscosity versus temperature plots for 20%/wt F127 and PF127 solutions.

[0201] FIG. 8 provide Ti values for F127 and PF127 solutions (left) and viscosity at 37° C., for 20% wt and 25% wt solutions.

[0202] FIG. 9 demonstrates the ability of the RTR device to gel in contact with tissue and the liquefy upon cooling.

[0203] FIGS. 10A-B show viscosity versus temperature plots of the F88 triblock and the PF88 chain extended polymer at various concentrations.

[0204] FIG. 11 depicts the two-step synthesis of a chain extended polymer comprising F127 and different Jeffamine segments.

[0205] FIG. 12 shows a fluoroscopic image showing free spillage of contrast material into the peritoneal cavity (thick arrow) after injection via the right fallopian tube (arrow), thereby confirming tubal patency.

[0206] FIG. 13 shows a fluoroscopic image demonstrating absence of contrast passage to the peritoneal cavity (arrow) following injection via the right fallopian tube, thereby confirming continued tubal occlusion. The distended uterine horn (reflux of contrast material) is clearly seen (thick arrow).

[0207] FIG. 14 provides fluoroscopic image taken following reversal of tubal occlusion in which a patent right fallopian tube is clearly seen following contrast injection (arrow) as is spillage of contrast into the peritoneal cavity (thick arrow), confirming tube patency.

[0208] FIGS. 15A-G depict the different stages of the implantation procedure at experiments performed using the chain extended PF88:15% RTR polymer: (A) Uterine horns and fallopian tubes of the rabbit; (B) Direct cannulation with a 24G Venflon catheter; (C) Injection of contrast dye prior to fallopian tube occlusion (D) Fluoroscopy confirmation of tubal patency; (E) Injection of sterile RTR Polymer (PF88 15%); (F) Injection of contrast dye after fallopian tube occlusion; (G) Fluoroscopy confirmation of tubal occlusion.

[0209] FIGS. 16A-E depict the different stages of the procedure 14-28 weeks later: (A) Direct cannulation with a 24G Venflon catheter; (B) Injection of contrast dye to test fallopian tube occlusion; (C) Fluoroscopy confirmation of tubal occlusion (D) Cooling the fallopian tube while injecting contrast dye; (E) Fluoroscopy confirmation of tubal patency.

DETAILED DESCRIPTION OF EMBODIMENTS

[0210] For sake of clarity, conciseness and simplicity, and without detracting from the generality of the technology in any form or fashion, the inventors have chosen to illustrate the invention by focusing on its use as an occlusion device suitable for deployment in the luminal cavity of the fallopian tubes, where the environmental stimulus is temperature. It is clear that the technology is equally applicable for occlusion of other lumens, utilizing materials as disclosed herein and stimuli that may be selected to meet a particular material composition or utility.

[0211] Some of the embodiments of the invention disclosed hereby will be exemplified using the family of polymers comprising poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) chains. These can be part of di or triblocks, such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblocks, commercially available as Pluronic©, {EO}.sub.99-{PO}.sub.67-{EO}.sub.99, and {EO}.sub.103-{PO}.sub.39-{EO}.sub.103, known as Pluronic F127 and Pluronic F88, respectively, being two leading examples.

[0212] Also, high molecular weight RTR polymers produced by covalently binding PEO-PPO-PEO triblocks using reactive bi-functional molecules such a di-isocyanates, di-acyl chlorides, phosgene, among others, were used as well. Among them, hexamethylene diisocyanate (HDI), may be used. Additionally, block polymers consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) segments, coupled via diverse coupling agents, such as di-isocyanates, di-acyl chlorides, di-carboxylic acids, phosgene, among others, were used as well. Other chemistries such as Michael addition, thiol-ene and click chemistry mechanisms may be used, among numerous others, as required.

[0213] [a] Synthesis of PF-127. Pluronic F-127 (molecular weight 12,600) was poured in a three-necked flask and dried. Then, the corresponding amount of HDI and SnOct.sub.2 (0.64 wt %) were added to the reaction mixture and reacted at 80° C. for 30 minutes under mechanical stirring (160 RPM) and dry nitrogen atmosphere. The polymer produced was dissolved in chloroform and precipitated in a petroleum ether 40-60 ethyl ether mixture (1:1). Finally, the polymer was washed repeatedly with portions of petroleum ether and dried. Different F-127/HDI ratios resulted in different degrees of polymerization (DP).

[0214] [b] Synthesis of Poly(ether-carbonate)s. These polymers were synthesized by copolymerizing poly(ethylene glycol) and poly(propylene glycol) segments utilizing phosgene as the coupling molecule. The different reactivity of phosgene's two functionalities allowed binding the two constituents, in both an alternate or random mode.

[0215] The synthesis of the alternating poly(ether-carbonate)s was carried out following a two-step reaction, as described elsewhere in detail. The first step was the PEO dichloroformate synthesis, followed by the reaction between the PEG derivative and the PPG chain, to produce the final block copolymer. The random poy(ether-carbonate)s were synthesized by a similar one-pot reaction, as described elsewhere in detail.

[0216] [c] Synthesis of Poy(ether-ester)s. The synthesis is exemplified hereby for a copolymer containing PEO6000 and PPO3000 segments. Equimolar amounts of dry PEG6000 and dry PPG3000 were dissolved in 30 ml dry chloroform in a 250 ml flask.

[0217] Triethylamine (2:1 molar ratio to PEG) was added to the reaction mixture, followed by the dropwise addition of the diacyl chloride (2:1 molar ratio to PEG) in dry chloroform over a period of 30 minutes at 40° C., under magnetic stirring. Then, the temperature was risen to 60° C. and the reaction was continued for additional 90 minutes. The polymer produced was separated from the reaction mixture by adding to it about 600 ml petroleum 14 ether 40-60. The lower phase of the two-phase system produced was separated and dried at RT. Finally, the polymer was thoroughly washed with petroleum ether and dried. Light yellow, brittle and water soluble powders were obtained.

[0218] [d] Synthesis of Poy(ether-ester-carbonate)s. The synthesis is exemplified hereby for a copolymer containing PEO6000 and PPO3000 segments, caprolactone blocks comprising four repeating units and phosgene. The (CL).sub.4-PEO6000-(CL).sub.4 triblock was synthesized as follows: 30.3 g of PEG6000 were dried at 120° C. under vacuum for 2 hours. Then, 10.1 g ε-caprolactone and 0.05 g stannous 2-ethyl-hexanoate were added. The reaction mixture was heated at 145° C. for 2.5 hours in a dry nitrogen atmosphere

[0219] Finally, the reaction mixture was cooled to room temperature, dissolved in chloroform, precipitated in petroleum ether and dried at room temperature. Once the (CL).sub.4-PEO6000-(CL).sub.4 triblock was obtained, the reaction with phosgene and the final reaction with the PPG chain were performed as described above.

[0220] In some instances, also biologically active molecules were added to the systems, by just blending them into one or more components of the occlusion device, including the RTR component. In other instances, it was covalently bound to the RTR component or the substrate, in the case the device comprises one.

[0221] Furthermore, an “on command” strategy” is easily implemented, whereby the occlusion device is cooled down in a controlled manner, so to allow the faster release of enhanced doses of the drug, at specific time points, as required clinically.

[0222] The basic building blocks of the RTR polymers developed are hydroxyl terminated polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) triblocks of various compositions and molecular weights. FIG. 1 present the generic formula of these triblocks. Even though several triblocks were used, most of the work described herein focuses on PEO.sub.99-PPO.sub.65-PEO.sub.99 and PEO.sub.102-PPO.sub.39-PEO.sub.102 triblocks, named F127 and F88, respectively. The F127 triblock has a molecular weight of 12,600 dalton and a 70% wt PEO content, while F88 has a molecular weight of 11,250 dalton and an 80% wt PEO content.

[0223] FIG. 2 lists the drawbacks of the existing triblocks. In light of the triblock's significant shortcomings, new RTR polymers displaying improved properties, including triblocks coupled via a suitable chain extender were prepared. As described below, several strategies were pursued seeking to generate occluders able to comply with the especially stringent requirements posed the fallopian tubes blocking plug.

[0224] One approach implemented related to the hydroxyl-terminated PEO-PPO-PEO triblocks as a monomeric diol that was then polymerized by reacting it with a chain extender, such as diisocyanates, typically hexamethylene diisocyanate (HDI). While the basic triblocks will be labelled “F”, the high molecular weight polymers are denominated “PF”. The synthesis of the resulting chain extended PF polyether urethanes is shown in FIG. 3.

[0225] The PF polymers formed were characterized initially by GPC, which demonstrated that the chain extension reaction took place producing polymers having different degrees of polymerization. The fact that actual polyether urethane backbones were generated was also proven by FT-IR and NMR spectroscopies, as exemplified in FIGS. 4A and B for F127 and the resulting PF127 chain extended polymer.

[0226] Expectedly, F127 as well as PF127 spectra show very large ether peaks around 1100 cm.sup.−1 due to the two hundred and sixty-five ether groups present in the F127 repeating unit. Of particular importance, though, is the peak at 1715 cm.sup.−1, absent in F127's spectrum but clearly shown by PF127, due to the urethane carbonyl group formed by the reaction between F127's hydroxyl end groups and HDI's isocyanate moieties. Additional strong evidence of the occurrence of the chain extension reaction was provided by NMR spectroscopy, as presented in FIG. 5. The key finding of the NMR spectrum pertains to the appearance of a new peak at 4.2 ppm. This absorbance band is assigned to the very last ethylene oxide unit present in the PEO segments that is now covalently bound to the just formed urethane group, causing the peak to shift from 3.6 ppm to 4.2 ppm.

[0227] On a morphological level now, the DSC thermograms shown in FIG. 6, show the effect of the polymerization of the PEO-PPO-PEO triblocks on the crystallizability of their semi-crystalline PEO segments. This is revealed by the fact that the melting peak of “monomeric” F127 shifted after the chain extension reaction from at 59° C. to 52° C. in PF127. Furthermore, the sharp melting endotherm shown by F127 has significantly broadened in PF127.

[0228] In accordance with theoretical considerations, the markedly larger PF127 chains formed solutions that, once gelled, attained much higher viscosity values, as shown in FIG. 7. It is also worth stressing that the PF127 solution has a lower Ti, the temperature of initiation of gelation, due to its higher molecular weight.

[0229] FIG. 8 presents the Ti values for F127 and PF127 solutions and the viscosity they attained at 37° C., for 20% wt and 25% wt solutions. The data showed in FIG. 8 shed light not only on the effect of the length of the chain, F127 versus PF127, on Ti and on the viscosity of the gel at body temperature, but also on the effect of the concentration of the RTR polymer on them.

[0230] FIGS. 9A-F illustrates the ability of the device to gel in contact with tissue and then liquefy upon cooling, the key feature that will allow the formation of the occlusion device by gelation and its removal by liquefication. Exemplified is an essentially 2D system in contact with a tissue of the hand, followed by its liquefaction by cooling. In this depiction, the RTR occluding formulation is poured (A) on the palm of the hand at a suitable temperature, below its relevant thermal sol-gel transition, so it is a solution, the viscosity of which can be tuned. Once in contact with the skin of the hand, loosely mimicking the luminal organ, the RTR solution heats up (B), crossing its thermal transition and gelling on the tissue (C-D). Subsequently, when required, the occluding gel is cooled down by various means, in this case using a cooling spray (E), whereby the gel is liquefied and easily and more importantly, non-injuriously removed from the site (F).

[0231] FIG. 10A depicts viscosity versus temperature plots of the F88 triblock, while FIG. 10B presents viscosity versus temperature plot of the PF88 chain extended polymer both at various concentrations. These figures demonstrate the enhanced rheological properties of the chain extended PF88 polymer.

[0232] Chain extended polymers comprising other groups, such as urea or amide groups along their backbone were synthesized. In one of the embodiments, urea functional groups were formed by reacting isocyanate and amine moieties.

[0233] Two synthetic strategies were pursued. In the first one, OH-terminated triblocks, such as F127 and F88, and amine-terminated molecules, such as, for example, Jeffamine chains of various molecular weights were mixed at different molar ratios and randomly chain extended with HDI. Seeking to generate a more ordered polymer expected to exhibit enhanced rheological properties, a two-stage synthetic scheme was followed, as described in FIG. 11. The polymers formed were denominated PFJ.

[0234] Initially, the F127 triblock was reacted in a 1:2 molar ratio with HDI, whereby the corresponding macrodiisocyanate was produced, which was subsequently chain extended using various amine-terminated molecules, such as various Jeffamines. Amides groups were generated along the polymeric chain by reacting isocyanate moieties with carboxylic acid groups, for example by oxidizing the hydroxyl end group of the triblocks to a COOH group and then chain extending the triblock with a diisocyanate, for example HDI.

In Vivo Work:

[0235] Eight female New Zealand rabbits of approximately -3.5 Kg weight were included in the study protocol. Briefly, under general endotracheal anesthesia the uterine horns and fallopian tubes were surgically exposed and cannulation of the distal uterine using a 24 Gauge Venflon needle catheter as standard, was performed in the direction of the fallopian tube. It should be stressed that all injections into the fallopian tubes were performed during simultaneous temporary occlusion of the uterine horn by external compression, in order to prevent reflux into the uterus. The tissues were maintained at approximately body temperature throughout, by external warming with pre-heated saline soaked gauze. Initially fallopian tubal patency was confirmed by injecting warmed saline and then water soluble iodinated contrast agent to demonstrate spillage into the peritoneal cavity under continuous fluoroscopic control (FIG. 12). The contrast agent was then flushed out using warm normal saline. Tubal occlusion was then performed by injecting ˜0.6 ml of the PF88:15% RTR polymer. Occlusion was confirmed by repeating the injection of warmed iodinated contrast material with fluoroscopic control by demonstrating lack of transit via the fallopian tube into the peritoneal cavity. The animals were then re-awakened and returned to the holding area.

[0236] Between 3.5 (n=2) and seven (n=3) months later the animals were returned to the experimental surgery laboratory and again using general endotracheal anesthesia the abdomen was opened surgically and the fallopian tubes/uterine horns were exposed, and maintained at ˜37° C., as described above. Following repeat cannulation of the tubes iodinated contrast material was injected to confirm tubal occlusion under fluoroscopic control (FIG. 13). The fallopian tubes were then individually exposed to iced water for the purpose of liquefying the occlusive polymer agent and achieve recanalization. The warmed contrast agent was once again injected under fluoroscopic control to confirm reversal of occlusion (FIG. 14). The animals were euthanized using standard approved techniques.

[0237] Histological analysis was performed on several specimens obtained after reversal of fallopian tube occlusion. There was no evidence of inflammation, infection or fibrosis is the specimens that were examined. Tube lumen appeared to be within normal limits with maintenance of patency (FIG. 15).

[0238] No major adverse events affecting the wellbeing of the animal subjects were encountered during the study period.

[0239] FIG. 16 shows the different stages of the procedure at experiments performed during using the same polymer 14-28 weeks later