Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1997-01-27
2001-10-30
Harrison, Robert H. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S484000, C424S422000, C424S423000, C424S424000, C424S425000
Reexamination Certificate
active
06309669
ABSTRACT:
III. FIELD OF THE INVENTION
This invention relates to compositions comprising active core material(s) such as biologically active agent(s), drug(s) or substance(s) encapsulated within an end-capped or a blend of uncapped and end-capped biodegradable-biocompatable poly(lactide/glycolide) polymeric matrix useful for the effective prevention or treatment of bacterial, viral, fungal, or parasitic infections, and combinations thereof. In the areas of general and orthopedic surgery, and the treatment of patients with infectious or chronic disease conditions, this invention will be especially useful to physicians, dentists and veternarians.
IV. BACKGROUND OF THE INVENTION
Wounds characterized by the presence of infection, devitalized tissue, and foreign-body contaminants have high infection rates and are difficult to treat.
To prevent infection, in bone and soft tissue systemic antibiotics must be administered within 4 hours after wounding when circulation is optimal. This has been discussed by J. F. Burke in the article entitled “The Effective Period of Preventive Antibiotic Action in Experimental Incisions and Dermal Lesions”,
Surgery
, Vol. 50, Page 161 (1961). If treatment of bacterial infections is delayed, a milieu for bacterial growth develops which results in complications associated with established infections. (G. Rodeheaver et al., “Proteolytic Enzymes as Adjuncts to Antibiotic Prophylaxis of Surgical Wounds”,
American Journal of Surgery,
Vol. 127, Page 564 (1974)). Once infections are established it becomes difficult to systemically administer certain antibiotics for extended periods at levels that are safe and effective at the wound site. Unless administered locally, drugs are distributed throughout the body, and the amount of drug hitting its target is only a small part of the total dose. This ineffective use of the drug is compounded in the trauma patient by hypovolemic shock, which results in a decreased vascular flow to tissues. (L. E. Gelin et al., “Trauma Workshop Report:Schockrheology and Oxygen Transport”,
Journal Trauma,
Vol. 10, Page 1078 (1970)).
Additionally, infections caused by multiple-antibiotic resistant bacterial are on the upswing and we are on the verge of a potential world-wide medical disaster. According to the Centers for Disease Control, 13,300 patients died in U.S. hospitals in 1992 from infections caused by antibiotic-resistant bacteria. Methicillin-resistant
S. aureus
(MRSA) is rapidly emerging as the “pathogen of the 90's”:
a. Some major teaching hospitals in U.S. report that up to 40% of strains of
S. aureus
isolated from patients are resistant to methicillin. Many of these MRSA strains are susceptible only to a single antibiotic (vancomycin).
b. Should MRSA also develop resistance to vancomycin, the mortality rate among patients who develop MRSA infections could approach 80%, thereby increasing the threat of this infectious killer.
Moreover, Vancomycin resistance is on the up-swing:
a. 20% of Enterococci are now resistant to vancomycin
b. In 1989, only one hospital in New York City reported vancomycin-resistant Enterococci. By 1991, the number of hospitals reporting vancomycin resistance rose to 38.
c. transfer of vancomycin-resistant gene (via plasmid) has been shown experimentally between Enterococcus and
S. aureus.
Many major pharmaceutical companies around the world have either completely eliminated or significantly reduced their research and development programs in the area of antibiotic research. According to a 1994 report by the Rockefeller University Workshop in Multiple Antibiotic Resistant Bacteria, we are on the verge of a “medical disaster that would return physicians back to the pre-penicillin days when even small infections could turn lethal due to the lack of effective drugs.”
Despite recent advances in antimicrobial therapy and improved surgical techniques, osteomyelitis (hard tissue or bone infection) is still a source of morbidity often necessitating lengthy hospitalization. The failure of patients with chronic osteomyelitis to respond uniformly to conventional treatment has prompted the search for more effective treatment modalities. Local antibiotic therapy with gentamicin-impregnated poly(methylmethacrylate) (PMMA) bead chains (SEPTOPAL TM, E. Merck, West Germany) has been utilized in Germany for the treatment of osteomyelitis for the past decade and has been reported to be efficacious in several clinical studies. The beads are implanted into the bone at the time of surgical intervention where they provide significantly higher concentrations of gentamicin than could otherwise be achieved via systemic administration. Serum gentamicin levels, on the other hand, remain extremely low thereby significantly reducing the potential for nephro- and ototoxicity that occurs in some patients receiving gentamicin systemically.
Since SEPTOPAL TM is not currently approved by the Food and Drug Administration for use in the United States, some orthopedic surgeons in this country are fabricating their own “physician-made beads” for the treatment of chronic osteomyelitis. A major disadvantage of the beads, however, is that because the PMMA is not biodegradable it represents a foreign body and should be removed at about 2-weeks postimplantation thereby necessitating in some cases an additional surgical procedure. A biodegradable-biocompitable, antibiotic carrier, on the other hand, would eliminate the need for this additional surgical procedure and may potentially reduce both the duration as well as the cost of hospitalization.
The concept of local, sustained release of antibiotics into infected bone is described in recent literature wherein antibiotic-impregnated PMMA macrobeads are used to treat chronic osteomyelitis. The technique as currently used involves mixing gentamicin with methylmethacrylate bone cement and molding the mixture into beads that are 7 mm in diameter. These beads are then locally implanted in the infected site at the time of surgical debridement to serve as treatment. There are, however, significant problems with this method. These include: 1) initially, large amounts of antibiotics diffuse from the cement but with time the amount of antibiotic leaving the cement gradually decreases to subtherapeutic levels; 2) the bioactivity of the antibiotic gradually decreases; 3) methylmethacrylate has been shown to decrease the ability of polymorphonuclear leukocytes to phagocytize and kill bacteria; 4) the beads do not biodegrade and usually must be surgically removed; and 5) the exothermic reaction that occurs during curing of methymethacrylate limits the method to the incorporation of only thermostable antibiotics (primarily aminoglycosides). Nevertheless, preliminary clinical trials using these beads indicate that they are equivalent in efficacy to longer term (4-6 weeks) administration of systemic antibiotics.
In many instances, infectious agents have their first contact with the host at a mucosal surface; therefore, mucosal protective immune mechanisms are of primary importance in preventing these agents from colonizing or penetrating the mucosal surface. Numerous studies have demonstrated that a protective mucosal immune response can best be initiated by introduction of the antigen at the mucosal surface, and parenteral immunization is not an effective method to induce mucosal immunity. Antigen taken up by the gut-associated lymphoid tissue (GALT), primarily by the Peyer's patches in mice, stimulates T helper cell (Th) to assist in IgA B cell responses or stimulates T suppressor cells (Ts) to mediate the unresponsiveness of oral tolerance. Particulate antigen appears to shift the response towards the (Th) whereas soluble antigens favor a response by the (Ts). Although studies have demonstrated that oral immunization does induce an intestinal mucosal immune response, large doses of antigen are usually required to achieve sufficient local concentrations in the Peyer's patches. Unprotected protein antigens may be degraded or may complex with secretory IgA in the intestinal lumen.
In the process of
Boedeker Edgar C.
Brown William
Cassels Frederick
Friden Phil
Jacob Elliot
Arwine Elizabeth
Harrison Robert H.
Nash Caroline
The United States of America as represented by the Secretary of
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