Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-11-16
2003-02-11
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06518308
ABSTRACT:
BACKGROUND OF THE INVENTION
It is well known that postoperative adhesions develop in the majority of patients following surgery. Adhesions can result in serious medical consequences and lifelong morbidity, including infertility, abdomino-pelvic pain, small bowel obstruction, and difficult reoperative procedures. Adhesions can manifest themselves shortly after the surgical procedure is performed, or many years thereafter, without any degree of predictability. Although adhesions are common in intraabdominal surgeries, adhesions can be a problem in virtually all types of surgeries. The haloorganic compounds of this invention, when formulated into pharmaceutical compositions, are useful in preventing or reducing the development of postoperative surgical adhesions, and therefore are of major clinical significance for the reduction of patient morbidity and mortality.
Postoperative surgical adhesions are generally believed to result from an injury or inflammation in the peritoneal cavity which produces a fibrous exudate. As a result of this exudate, the serosal tissue surfaces stick together. The fibrous exudate may be absorbed or invaded by fibroblasts to form a permanent fibrous adhesion.
Removal of fibrin before it is invaded by fibroblasts can prevent the development of permanent fibrous adhesions. Removal of fibrin occurs due to the fibrinolytic activity of the peritoneal cavity. Fibrinolytic activity can vary as a result of surgery, but it is absent from a peritoneal wound during the first 48 hours following surgery. However, there is a gradual increase in fibrinolytic activity after this time for up to eight (8) days when the peritoneum heals.
The mechanisms of peritoneal healing, and the alterations which result in postoperative adhesion development, are not well understood. Compositions which are currently approved by the U.S. FDA for use in the reduction of intraperitoneal adhesions theoretically serve as adhesion barriers that separate opposing, potentially adherable sites during the critical three to five day period of peritoneal repair.
Such compositions, including Intercede™, which is manufactured and sold by Johnson and Johnson, and Seprafilm™, which is manufactured and sold by Genzyme Corporation, are resorbable. i.e. reabsorbed in the surrounding tissue, and have been shown in clinical trials to reduce adhesions at the site where they are placed during a laparotomy. However, there is no clinical evidence that these compositions are of any benefit at sites within the patient removed form the site of application for the reduction of de novo adhesion formation, or for the reduction in adhesion reformation at such other sites. Similarly, there is no convincing clinical evidence that these materials are efficacious for surgical procedures performed by laproscopy, perhaps in part due to the difficulty in laproscopic placement of the material.
PCT published patent application WO 00/20642, published Apr. 13, 2000, discloses methods for the prevention of adhesion development by the administration of therapeutic formulations containing TIMP-1 antibodies to a patient. TIMP-1 is part of a family of inhibitors of metalloproteinase proteins, or TIMP's, which regulate the catalytic activity of matrix metalloproteinases (MMP's). The administration of antibodies to TIMP-1 to a patient is believed to alter the local levels of both TIMP-1 and MMP, and specifically to reduce the expression of TIMP-1, to thereby inhibit the development of adhesions.
Accordingly, there is perceived to be a need for an improved method for adhesion control and prevention which can be conveniently administered to a patient, and which is not restricted to the site of a particular surgical procedure. There is a particular need for such an, improved method which can also be used in connection with the rapidly growing field of laproscopic surgeries, and at sites throughout the body in addition to the abdominal cavity.
SUMMARY OF THE INVENTION
The present invention relates to methods for preventing or reducing the development of surgical adhesions, and compositions which can be used in such methods.
In one aspect, the invention includes a pharmaceutical formulation for preventing or reducing the development of surgical adhesions. The formulation contains, as an active ingredient, a halogenated organic compound of formula CR
1
OOR
2
, wherein R, is an alkyl group of 1 to 4 carbons, or a haloalkyl group of 1 to 4 carbons, and wherein R
2
is selected from the group consisting of hydrogen, halogen, lower alkyl and lower haloalkyl, provided that either R
1
or R
2
must contain at least one halogen. The pharmaceutical formulation can also include suitable pharmaceutically acceptable carriers and adjuvants, as well as other therapeutic compounds which assist in the prevention of adhesions. The term “pharmaceutically acceptable carrier” denotes a carrier substance that potentiates, and does not significantly diminish, the effect of the active agent in the body.
The terms “prevent” and “preventing” as used herein refer to inhibiting completely or partially a biological response, as well as inhibiting an increase in a biological response. For instance, prevention of adhesion development refers to partially or completely inhibiting adhesion formation and adhesion reformation, as well as inhibiting an increase in adhesion formation and adhesion reformation.
In a preferred embodiment, the halogenated compound of this invention is a halogenated acetic acid derivative, more preferably dichloroacetic acid or 2-chloropropionate. Prodrugs which form the halogenated compounds in the body can also be used, and are included within the scope of this invention. Additional modifications embraced by this invention include carriers which can be used to bind the halogenated compounds prior to administration, and which subsequently release the halogenated compounds in the body in active form. Suitable biocompatible carriers are well known to those skilled in the art.
Typically, the pharmaceutical composition of the invention contains from about 1% to about 50% active ingredient, and preferably from about 2% to about 10% active ingredient. Human dosages in the range of from about 10 mg/kg to about 100 mg/kg can be used depending on the severity of the particular condition and the treatment protocol.
The pharmaceutical composition can be delivered to the subject by any route known in the art. For instance, the pharmaceutical composition can be administered systemically, such as orally or parenterally, or it may be administered locally. The pharmaceutical composition can also be delivered in a sustained release device. Alternatively, the pharmaceutical composition can be administered with an anti-adhesion adjuvant to obtain the benefits of a barrier compound and the adhesion prevention composition. The adjuvant may be used in the form of a gel, liquid or a solid membrane. Typical anti-adhesion adjuvants which are useful in this invention include commercial products such as Intercede® and Seprafilm®.
In another aspect, this invention includes a method for preventing or reducing the development of surgical adhesions by treating a patient at risk of developing such adhesions with a therapeutic formulation containing, as an active ingredient, a halogenated organic compound of formula CR
1
OOR
2
, wherein R
1
is selected from the group consisting of lower alkyl groups (of 1 to 4 carbons), or lower haloalkyl groups, and wherein R
2
is selected from the group consisting of hydrogen, halogen, lower alkyl and lower haloalkyl, provided that either R
1
or R
2
must contain at least one halogen atom.
Although it is most common to use the pharmaceutical compositions of this invention for peritoneal surgery, the type of surgery in which the product is used may be any type where there is a risk of developing surgical adhesions associated with the surgery. In some embodiments, the subject can undergo a surgery selected from the group consisting of abdominal surgery, gynecological surgery, cardiac surgery, back surgery, neurosurgery, ligament a
Jarvis William R. A.
Kim Vickie
Ropes & Gray
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