Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Ophthalmic preparation
Reexamination Certificate
1999-11-12
2003-10-07
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Ophthalmic preparation
C514S023000, C514S025000, C514S035000, C514S036000, C514S054000, C514S082000, C514S192000
Reexamination Certificate
active
06630135
ABSTRACT:
BACKGROUND OF INVENTION
The present invention relates to sustained release pharmaceutical compositions containing one or more antibiotics. The invention is also directed to the use of such compositions to sterilize the tissues in the area of surgery (i.e., the “surgical field” or “field of surgery”) prior to a surgical procedure and to prevent post-surgical infections.
Ophthalmic surgical procedures currently involve the topical application of betadine solution to the eyelid and other tissues adjacent to the eye prior to surgery. The preoperative procedures may also include topical instillation of argyrol to facilitate removal of mucus and other debris present on the cornea and conjunctiva. However, the foregoing procedures do not result in sterilization of the ophthalmic tissues which form the site of the surgery (e.g., the cornea, sclera or various other ophthalmic tissues).
Antimicrobial agents such as the aminoglycosides, penicillins and cephalosporins, being relatively insoluble in lipids, penetrate the eye poorly after systemic administration. Therefore, the surgical field is currently sterilized by subconjunctival injection of any one of various antibiotics. The most commonly used drug in subconjunctival injection is gentamicin (about 30 mg per injection). This method involves the insertion of a 20 gauge needle into the subconjunctival space, taking care not to pierce the conjunctiva; 0.1 ml to 1.0 ml of antibiotic is injected. This technique permits significant antibiotic to enter the corneoscleral limbus near the subconjunctival injection site. However, such injections present a significant risk of injury to ophthalmic tissues if performed improperly. Even when proper procedures are followed, such injections are painful and inherently involve at least some undesirable trauma due to the passing of the hypodermic needle through very delicate ophthalmic tissues. In addition, subconjunctival injections of antibiotics can result in nonuniform concentrations of the antibiotics in the cornea, and the concentrations attained may be inadequate. For example, the maximum gentamicin concentration attained in the aqueous humor of rabbits from subconjunctival injection is 8.8 ug/g. Although a concentration of 8.8 ug/g would be effective against some bacteria, a significantly higher concentration is required for more resistant strains. Still another problem is the fairly recent development of bacterial resistance to aminoglycoside antibiotics.
The intravenous (“IV”) and oral dosage of quinolones have been suggested for prophylactic usage and as an alternative to subconjunctival injections. However, the maximum aqueous humor concentration from IV injection (200 mg) and oral dosage (1 g) of ciprofloxacin in humans is 0.16 ug/ml and 0.33 ug/ml, respectively, at one hour after administration. This is less than its MIC90 (0.5 ug/g). These non-ocular delivery routes are also associated with higher risks of systemic side effects. The topical application of existing antibiotic formulations is useful in cases of superficial infections, but is inadequate for the delivery of high concentrations of antibiotics to deeper eye tissues prior to surgery.
This risk of infection subsequent to ophthalmic surgery is a significant concern. The post-surgical application of an antibiotic is therefore normally desirable. However, as with the current procedures for sterilizing the ophthalmic field prior to surgery, the post-surgical administration of antibiotics by means of hypodermic injections has significant drawbacks.
Accordingly, improved methods of sterilizing ophthalmic tissues prior to surgery and preventing post surgical infections are needed
SUMMARY OF THE INVENTION
The present invention is directed to the use of sustained release antibiotic compositions to sterilize the field of surgery prior to ophthalmic surgical procedures and prophylactically treat post-surgical infections. The invention has significant advantages relative to prior methods of sterilizing the field of surgery and prophylactically treating post-surgical infections. The principal advantages are as follows: (1) the drug is more evenly distributed; (2) a MIC is achieved fairly rapidly; (3) the drug has a longer residence time in the cornea and other ophthalmic tissues; and (4) the pain, trauma and inherent hazards of hypodermic injections are avoided.
The compositions of the present invention comprise one or more antibiotics in a sustained-release vehicle. The preferred antibiotics are quinolones (e.g., ciprofloxacin). The preferred vehicle is a viscous gel. Other types of vehicles which provide for a sustained release of the antibiotics, such as a solid insert which is placed in the cul-de-sac of the eye and then gradually erodes as it is bathed with ocular fluids, may also be used.
It has been found that the compositions of the present invention enable potent, ophthalmically acceptable antibiotics to penetrate the anterior chamber of the eye in concentrations that are bactericidal relative to most gram-negative and gram-positive organisms. The sustained-release of antibiotics from the compositions of the present invention enables the therapeutic objectives of sterilizing the surgical field and preventing post-surgical infections to be accomplished by means of a single application of the compositions topically to the eye.
DESCRIPTION OF PREFERRED EMBODIMENTS
The antibiotics which may be used in the present invention include all antibiotics which: (1) have potent, broad activity against ophthalmic pathogens; (2) are at least partially water soluble; (3) are capable of penetrating the corneal epithelium; and (4) are nontoxic to ophthalmic tissues. Antibiotics which satisfy the foregoing criteria are referred to herein as being a “potent, ophthalmically acceptable antibiotic”. The potent, ophthalmically acceptable antibiotics utilized in the present invention preferably have a minimum inhibitory concentration (“MIC”) against common ophthalmic pathogens of four micrograms per milliliter (4 mcg/ml), or less. Also, the minimum bactericidal concentration (“MBC”) of these antibiotics, relative to specified ophthalmic pathogens, is preferably no more than two times greater than the minimum inhibitory concentration thereof.
The most preferred antibiotics are quinolones. Aminoglycosides are also preferred. Both of these classes of antibiotics are well known. Representative examples of antibiotics from each of these classes are presented below:
Quinolones
Aminoglycosides
Ciprofloxacin
Gentamicin
Ofloxacin
Tobramycin
Norfloxacin
Other classes of antibiotics which may be utilized include cephalosporins and penicillins. Further examples of antibiotics which may be used are listed below:
Amikacin
Cephalothin
Methicillin
Ampicillin
Chloramphenicol
Oxacillin
Carbenicillin
Clindamycin
Penicillin GK
Cefazolin
Colistin
Piperacillin
Cefoxitin
Erythromycin Lactobionate
Streptomycin
Ceftazidime
Imipenem
Ticarcillin
Cefotaxime
Kanamycin
Vancomycin
The concentration of antibiotic utilized in the compositions of the present invention will vary depending on the intended use of the compositions (i.e., sterilization of the surgical field or prevention of post-surgical infections), and the relative antimicrobial activity of the specific antibiotic selected. The antimicrobial activity of antibiotics is generally expressed as the minimum concentration required to inhibit the growth of a specified pathogen. The concentration is also referred to as the “minimum inhibitory concentration” or “MIC”. The term “MIC90” refers to the minimum concentration of antibiotic required to inhibit the growth of ninety percent (90%) of a population of multiple strains of a microorganism. The concentration of an antibiotic required to totally kill a specified population of bacteria or other pathogens is referred to as the “minimum bactericidal concentration” or “MBC”.
The minimum inhibitory concentrations of some of the preferred antibiotics of the present invention, relative to a specific strain of
Pseudomonas aeruginosa
(i.e., Strain 4N3422), are presented in the following tabl
Cagle Gerald D.
Ke Tai-Lee
Lorenzetti Ole J.
Schlech Barry A.
Alcon Laboratories Inc.
Brown Gregg C.
Peselev Elli
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