Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1995-05-22
2002-06-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S502000, C428S402240, C514S772300
Reexamination Certificate
active
06410056
ABSTRACT:
III. FIELD OF THE INVENTION
This invention relates to antibacterial antibiotics encapsulated within a biodegradable polymeric matrix.
IV. BACKGROUND OF THE INVENTION
One of the most difficult types of wounds to treat is characterized by the presence of infection, devitalized tissue, and foreign-body contaminants. Local application of encapsulated antibiotics to an area infected with bacteria provides immediate, direct, and sustained dosing which targets the antibiotic to the wound site (soft or hard tissue), and minimizes problems inherent in systemic drug administration. Additionally, by encapsulating antibiotics and applying them directly to the wound site one sees a significant reduction of nonspecific binding of drug to body proteins a phenomena that is commonly observed following the systemic administration of free drugs that are in route to infected site.
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 hypoyolemic 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 bacteria are on the up-swing 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%.
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 r & d 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 treatmnent modalities. Local antibiotic therapy with gentamicin-impregnated poly(methylmethacrylate) (PMMA) bead chains (SEPTOPAL™, 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™ 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 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 long term (4-6 weeks) administration of systemic antibiotics.
V. SUMMARY OF THE INVENTION
This invention relates to a novel pharmaceutical composition, a micro- or macrocapsule/sphere formulation, which comprises an antibiotic encapsulated within a biodegradable polymeric matrix such as poly (DL-lactide-co-glycolide) (DL-PLG) and its use in the effective pretreatment of animals to prevent bacterial infections and the posttreatment of animals (including humans) with bacterial infections. Microcapsules and microspheres are usually powders consisting of spherical particles of 2 millimeter or less in diameter, usually 500 micrometer or less in diameter. If the particles are less than 1 micron, they are often referred to as nanocapsules or nanospheres. For the most part, the difference between microcapsules and nanocapsules is their size; their internal structure is about the same. Similarly, the difference between microspheres and nanospheres is their size; their internal structure is about the same.
A microcapsule (or nanocapsule) has its encapsulated material, herein after referred to as agent, centrally located within a unique membrane, usually a polymeric membrane. This membrane may be termed a wall-forming material, and is usually a polymeric material. Because of their internal structure, permeable microcapsule
Jacob Elliot
Setterstrom Jean A.
Tice Thomas R.
Arwine Elizabeth
Harris Charles H.
Howard S.
Moran John Francis
Page Thurman K.
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