Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-06-22
2001-08-28
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S486000, C424S423000, C424S078370, C424S487000, C424S488000, C424S484000
Reexamination Certificate
active
06280745
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to pharmaceutical preparations and methods of their use. More particularly, the present invention relates to preparations suitable for the reduction of adhesion formation in mammals or the delivery of pharmaceutically active compounds.
BACKGROUND OF THE INVENTION
Over the years, methods have been developed to achieve the efficient delivery of therapeutic or diagnostic agents to a mammal requiring such treatment. Aqueous liquids which can be applied at room temperature in a free flowing state but which forms a semi-solid gel when warmed to body temperature have been used in such capacities for some time. Such systems combine ease of application with greater retention at the site of application than the use of exclusively free flowing vehicles. For example, in U.S. Pat. No. 4,188,373, incorporated herein by reference, Pluronic® polyols are used in aqueous compositions to provide thermally gelling aqueous systems. Adjusting the concentration provides the desired sol-gel transition temperature. More particularly, the lower the concentration of the incorporated polymer the higher the sol-gel transition temperature. At a critical polymer concentration minimum, the system reaches a point where a gel will not form at any physiologically compatible temperature. While such vehicles are a substantial improvement over prior art systems, it is hard to precisely adjust the sol-gel temperature to the desired value.
In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822, each incorporated herein by reference, drug delivery systems are described which utilize thermosetting gels. In these systems both the gel transition temperature and/or rigidity of the gel may be modified by adjustment of the pH and/or the ionic strength as well as by the concentration of the polymer. Although such vehicles may be efficiently used for the delivery of bioactive agents, establishment and maintenance of the desired sol-gel temperature and/ or persistence of the gel may be complicated by several variables including the localized physiology of the mammalian subject. Accordingly, a need still exists for pharmaceutical preparations or drug delivery compositions that allow for the establishment of a precise sol-gel transition temperature and accurate control of the gel dissolution rate in vivo.
Control of such characteristics is also desirable when similar polymeric gels are used for the prevention of adhesion formations in mammals. Adhesions are thought to form following a trauma or injury to the peritoneum. This results in increased vascular permeability, which produces an inflammatory exudate and results in the formation of a fibrin matrix. In normal wound healing, the fibrin matrix is removed by fibrinolysis, and subsequent fibroblast proliferation results in remesothelialization. However under the ischemic conditions present following surgical trauma the fibrinolytic process is suppressed and the fibrin matrix may persist. If it persists until about day three, significant collagen deposition within the fibrin matrix, can lead to adhesion formation.
As will be appreciated by those skilled in the art, prevention of adhesions has been the subject of various efforts since the beginning of this century (see, for example,
Surgery, Gynecology and Obstetrics,
133:497-509, 502-503 (1971)). These efforts have included means of preventing the fibrin-coated walls of the intestine from contacting one another by distending the abdomen with oxygen or filling the abdomen with various liquids such as saline solution, paraffin, olive oil, lanolin, concentrated dextrose solution, various macromolecular solutions and silicones.
High molecular weight dextran either alone or in combination with dextrose has also been used (Holtz, et al.,
Fertility and Sterility,
33:660-662 (1980); 34:394-395 (1980)). One such formulation, HYSKON® (Pharmacia, Piscataway, N.J.), which comprises 32% aqueous solution of dextran 70 containing 10% dextrose, was effective in reducing peritoneal adhesions subsequent to surgery. However, it has been reported that HYSKON has a tendency to support bacterial proliferation. Further concern has been expressed over the anaphylactoid potential of dextran (DiZerega et al.,
Fertility and Sterility,
40:612-619 (1983)). In addition, the benefit of dextran 70 in preventing post-operative adhesions was shown to be limited to the more dependent regions of the pelvis.
The use of resorbable fibrous barriers to separate injured tissues has also been described (Linsky,
J. Reprod. Med.,
17-20 (1987)). For example, TC-7 (Johnson and Johnson Products, Inc., New Brunswick, N.J.), an oxidized cellulose fabric barrier, has been used as a treatment to prevent organ adhesion to the peritoneum. Other solid sheet devices include polytetrafluoroethylene (Gore-Tex®, W. L. Gore) and crosslinked hyaluronic acid (Seprafilm®Genzyme Corp.).
Chondroitin sulfate and sodium carboxymethyl cellulose have also been used to prevent the formation of postoperative adhesions in the rabbit uterus (Oelsner et al.,
J. Reprod. Med.
32:812-814 (1987)). Chondroitin sulfate solutions have also been proposed for intraperitoneal use in the prevention of adhesions in rabbits.
More recently, aqueous gel compositions comprising polyalkylene polymers have been shown to successfully reduce adhesions (U.S. Pat. No. 5,366,735, incorporated herein by reference). These compositions can be applied below room temperature as a liquid and form semi-solid gels when warmed to body temperature. However, as with the aforementioned drug delivery compositions, precise control of the sol-gel transition temperature and dissolution rate of the gel within the physiological environment still present problems in many cases. Accordingly, despite these previous efforts, a need exists for improved means to treating and/or preventing post-surgical adhesions.
As such, it is an object of the present invention to provide polymeric gel compositions which allow for precise control of the sol-gel transition temperature and/or dissolution rate of the gel once formed.
It is a further objective of the present invention to provide gelling drug delivery preparations, and methods for their use, comprising at least one bioactive agent and exhibiting desired sol-gel transition temperatures and/or gel dissolution rates.
It is yet another objective of the present invention to provide gelling compositions, and methods of their use in preventing or reducing adhesions, which exhibit desired sol-gel transition temperatures and/or gel dissolution rates.
SUMMARY OF THE INVENTION
The present invention accomplishes these and other objectives by providing polymeric compositions that exhibit well defined sol-gel transition temperatures (or defined ranges of temperatures) and/or established dissolution rates. In one embodiment, the disclosed compositions generally comprise at least one constitutive polymer and at least one modifier polymer that may be used to modify or control the dissolution rate of gel once it has been formed. In another preferred embodiment, the compositions of the present invention comprise at least one constitutive polymer and at least one hydrophilic co-surfactant whereby the gelation temperature (or sol-gel transition temperature) of the composition may be controlled or modified. Of course, it will be appreciated that the compositions may comprise at least one constitutive polymer in combination with both at least one modifier polymer and at least one hydrophilic co-surfactant to provide preparations having both selected gelation temperatures and superior dissolution times. Yet other preferred embodiments of the invention will comprise the aforementioned preparations and at least one bioactive agent. In any event, the polyphase preparations of the present invention may be used to retard or prevent the formation of scar tissue or adhesions in a mammal, for the prolonged delivery of a bioactive agent or both.
Accordingly, in selected embodiments the present invention comprises methods for the reduction of adhesio
Dellamary Luis A.
Flore Stephen G.
Reeve Lorraine E.
Weers Jeffry G.
Alliance Pharmaceutical Corp.
Fubara Blessing
Page Thurman K.
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