Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-26
2002-07-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S484000, C424S486000, C424S487000, C424S489000, C424S078080, C424S078170, C424S078240
Reexamination Certificate
active
06423332
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to compositions that are used in methods of deforming a selected tissue structure for treatment of e.g., incontinence, vesicoureteral reflux, or gastroesophageal reflux.
BACKGROUND OF THE INVENTION
In the recent past, urinary incontinence has been successfully treated by using minimally invasive surgical means. One method which has been used to treat patients with urinary incontinence is periurethral or transurethral injection of a composition commercially sold in Canada as “Polytef” and as “Urethrin.” “Polytef” is a paste comprising a fifty-fifty (50/50) by weight mixture of glycerine liquid and PTFE particles. However, after injection, over a period of time the glycerin is readily dissipated into the body and then metabolized or eliminated, leaving only the PTFE particles. This means that only fifty (50) percent of the injected weight remains at the injection site. Consequently the surgeon must inject significantly more volume than necessary and at times may inadvertently coapt the urethra further than is desired. This closure could possibly be complete and thus place the patient into temporary urinary retention. Additionally, the fact that a large portion of the injected volume disappears makes it difficult for the surgeon to visually gauge how much is an appropriate amount of the PTFE paste to inject. As a result, the surgeon is likely not to inject enough paste volume. The procedure therefore may fail, and multiple procedures to inject additional paste may be required. An additional drawback of the PTFE paste is that the PTFE particle size is sufficiently small so as to allow the particles to migrate to other locations of the body such as the lungs, brain, etc. PTFE particles have been known to induce tissue reaction and form PTFE-induced granulomas in certain individuals. This tissue reaction to PTFE has caused concerns for the patient's safety. Also, the PTFE paste is highly viscous and can only be injected by applying a large injection force (IF). Often this is accomplished by utilizing an injection assist device in order to deliver the highly viscous PTFE paste through a needle of any acceptable size at acceptable flow rates.
An alternative to using the PTFE paste is using a collagen suspension. The collagen suspension is injected in the same manner as PTFE paste so as to form a fibrous mass of tissue around the augmentation site. This fibrous mass created by the collagen injection, however, decreases in size and breaks down over time as it is eventually degraded by the patient's body. As a result, additional injections are periodically required.
Another alternative is to inject silicone particles dispersed in an aqueous, polyvinylpyrrolidone (PVP) solution. This combination has the same problems as the PTFE paste, in that the polyvinylpyrrolidone solution is readily dissipated away from the area of injection, leaving only the volume of silicone particles remaining and, in that, due to its high viscosity, a great deal of force is necessary to inject the silicone dispersion through a needle of an acceptable size, whereby it is necessary for the surgeon to utilize an injection assist device to accomplish injection.
Another material that has been injected is autologous fat. This has had similar problems as the collagen, in that the body eventually breaks it down and it disappears. The act of harvesting the autologous fat and processing it for injection is also time consuming and provides variable levels of clinical improvement.
Devices have been made to attempt to overcome these problems. One device is an inflatable silicone sphere that is passed through a needle and is inflated with PVP in the same area that the other materials are injected. There are, however, some problems associated with this device. It is a delicate, mechanical device that is capable of mechanical failure of the valves, shells and structural joints. Also disadvantageous are the fixed geometry of the sphere, potential migration along the implantation tract, or extrusion of the device through the periurethral tissues.
Hydrogel particles provide desirable mechanical and tissue response properties; however they need to be resuspended in a nonaqueous carrier for injection. This allows for easy injection of small, dehydrated particles, which can later swell, in-situ following clearance of the carrier. These injectable suspensions suffer from the defect of particle settling and separation as the composition is stored for long periods of time. The settling is driven by the inherent density differences between particles and carrier. This phenomenon requires that the suspension therefore either be mixed or remixed at the time of use to obtain a uniform suspension at the time of injection. The mixing requirement is both inconvenient, can necessitate the need for additional equipment, and if not performed thoroughly can lead to uneven placement of particles when inserted into tissues, therefore possibly providing a poor procedure result. Also disadvantageous is the potential for the settled particles to clog the needle during injection. Berg, et al., in U.S. Pat. No. 5,007,940 have made an attempt to overcome the problems enumerated above by utilizing densely packed, fully hydrated hydrogel particles in disk form which deform as they pass through a needle during injection. The dense packing of the particles eliminates problems of particle settling since neighboring particles touch each other and thereby support the weight of particles above them. This art teaches that the deformability of hydrogel particles is sufficient to allow injection with dense packing (i.e., no free carrier liquid). The manufacture of the particles described in patent #5,007,940 is complex and costly and they have not been utilized commercially. Also the densely packed particles, despite their high degree of deformability, have still exhibited a relatively high viscosity whereby their use has required the use of relatively large internal diameter needles and the use of relatively large injection forces to accomplish insertion in a patient.
Van Bladel et al., in U.S. Pat. No. 5,813,411 disclose that injection of a densely packed suspension of hydrogel particles is made easier when an organic agent is added to the aqueous liquid swelling the particles. Our attempts to practice this embodiment, without the incorporation of excess suspending liquid have still presented several challenges. Most significantly, the organic additives dehydrate and shrink the particles, yet upon clearance of the dehydrating organic in the body the implant will swell to a volume larger than what was originally injected. This can cause serious problems in urethral augmentation where the additional swelling of the implant can cause closure of the urethra leading to difficulty in urination or even retention. In addition, high stresses exerted on densely packed particles as they are forced into the hub of needles during the injection process can lead to particle fracture. This is particularly significant for highly swollen hydrogels and for those exhibiting brittleness. Further dehydration of the particles by the addition of more organic either leads to particle settling when the particles become severely dehydrated or exacerbates the excess in-situ swelling of the implant or increases to required injection force. The settling also increases the opportunity of needle clogging during implantation.
Wallace et al., in U.S. Pat. No. 4,803,075 teach the addition of a polymer lubricant to an aqueous suspension of particles to reduce injection forces for injectable particulate soft tissue bulking agents. This additive to a carrier liquid does not prevent settling of particles from solution during storage and hence can still require remixing a suspension at the time of use.
Accordingly, it would be desirable to have a composition that is ready to inject at the time of use, without having to reconstitute it or use an injection assist device to inject it. Also, it would be desirable to have a composition that will not
Huxel Shawn T.
Kataria Ram L.
Rosenblatt Joel S.
Di Nola-Baron Liliana
Ethicon Inc.
Page Thurman K.
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