Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-02-22
2004-02-24
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S235800, C424S427000
Reexamination Certificate
active
06696426
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition in an aqueous solution form useful for administration to an eye of a subject for treatment or prevention of infectious disease therein. In particular, the present invention relates to such a composition having as an active agent an oxazolidinone antibiotic drug. The field of the present invention also includes therapeutic or prophylactic use of such a composition, and use of such a composition in preparation of a medicament.
BACKGROUND OF THE INVENTION
Numerous oxazolidinone compounds have been reported as having therapeutically and/or prophylactically useful antibiotic or antimicrobial, in particular an antibacterial, effect. Among such compounds are those illustratively disclosed in the following patents, each of which is individually incorporated herein by reference.
U.S. Pat. No. 5,164,510 to Brickner.
U.S. Pat. No. 5,231,188 to Brickner.
U.S. Pat. No. 5,565,571 to Barbachyn & Brickner.
U.S. Pat. No. 5,627,181 to Riedl et al.
U.S. Pat. No. 5,652,238 to Barbachyn et al.
U.S. Pat. No. 5,688,792 to Barbachyn et al.
U.S. Pat. No. 5,698,574 to Riedl et al.
U.S. Pat. No. 6,069,145 to Betts.
Compounds disclosed in above-cited U.S. Pat. No. 5,688,792 include for example the compound (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, referred to herein as “linezolid.” Linezolid has the structure shown in formula (I):
and is in commercial use as a medicament under the trademark Zyvox® of Pharmacia Corporation. Linezolid exhibits strong antibacterial activity against gram-positive organisms including those of the following genera: Staphylococcus (e.g.,
Staphylococcus aureus, Staphylococcus epidermidis
), Streptococcus (e.g.,
Streptococcus viridans, Streptococcus pneumoniae
), Enterococcus (e.g.,
Enterococcus fecalis, Enterococcus faecium
), Bacillus, Corynebacterium, Chlamydia and Neisseria.
Many such gram-positive organisms have developed significant levels of resistance to other antibiotics. Oxazolidinone antibiotics are also generally effective against anaerobic organisms such as those of the genera Bacteroides and Clostridia, and against acid-fast organisms such as those of the genus Mycobacterium.
Above-cited U.S. Pat. No. 5,688,792 discloses that antibiotic oxazolidinone compounds, including linezolid, can be formulated as a gel or cream for topical application to skin.
Many oxazolidinone compounds useful as antibiotics do not form, or do not readily form, salts. For these compounds, and where for any reason it is preferred not to provide the antibiotic in salt form, it is generally difficult to formulate the antibiotic as a solution in a pharmaceutically acceptable liquid carrier, particularly an aqueous carrier. Most such compounds have relatively low solubility in water. In the case of linezolid, for example, the solubility at ambient temperature is less than 3 mg/ml and the practical limit of concentration in aqueous solution is about 2 mg/ml.
Where ophthalmic administration of an oxazolidinone antibiotic drug is contemplated, it is desired to achieve sufficiently high concentrations of the drug to be therapeutically effective in treating eye infections while ensuring all or substantially all of the drug is in solution. Undissolved, particulate, forms of any ingredient of an ophthalmic solution can cause irritation upon administration to the eye of a subject. Some have approached the problem of a need to administer drugs with low solubility to an eye by providing sufficiently dilute aqueous ophthalmic solutions of a poorly soluble drug to ensure that the drug is in solution. Such dilute solutions of drug must be administered to an eye more frequently than would a higher concentration solution of the same drug, were it possible to make such a solution.
Use of dilute solutions of oxazolidinones is disclosed in U.S. Pat. No. 6,337,329 B1 (International counterpart published as WO 00/03710), incorporated herein by reference. The patent, specifically, discloses a method of treating bacterial keratitis or bacterial conjunctivitis in an eye, comprising topical administration of an oxazolidinone antibiotic to the infected eye. Preferred oxazolidinone compounds for use according to the method of WO 00/03710 include (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (linezolid) and (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (eperezolid). The oxazolidinone compound is said to be administered in a formulation such as a solution, cream, ointment, emulsion, suspension or slow release formulation, a solution being preferred. Ophthalmic formulations exemplified therein include 10% and 12% weight/volume solutions of linezolid. At such low concentrations of linezolid, it is further disclosed in U.S. Pat. No. 6,337,329 B1 that the oxazolidinone compound can be used individually, in combination with another oxazolidinone compound, in combination with other antibacterial agents, or in combination with non-antibacterial agents.
International Patent Publication No. WO 00/18387, incorporated herein by reference, discloses additional dilute aqueous ophthalmic compositions comprising an oxazolidinone antimicrobial agent. Preferred oxazolidinone compounds according to WO 00/18387 are those of above-cited U.S. Pat. No. 5,627,181. The oxazolidinone component of the compositions was disclosed to typically be present in a concentration of from about 0.1 to about 1.0 percent by weight of the composition (p. 8). The international patent publication also disclosed that the compositions can further comprise an anti-inflammatory agent.
Where ophthalmic administration of an oxazolidinone antibiotic drug is contemplated, it is desired to be able to administer a pharmaceutically effective dose in as small a volume as possible, without having anything in the ophthalmic solution likely to irritate the eye. It will readily be understood that it is difficult to achieve such concentrations by administration of a relatively small volume of a composition wherein the drug is present in dissolved form, unless the composition has a relatively high drug loading, and in particular a drug loading substantially above the limit of solubility in water of most oxazolidinone antibiotics not in the form of a salt.
Derivatives of cyclodextrin, including &agr;-, &bgr;, and &ggr;-cyclodextrins and derivatives thereof, such as ether and mixed ether derivatives, and derivatives bearing sugar residues have been disclosed as being suitable for use in the solubilization of various drugs that are only sparingly soluble in water. EP 0149 197 B2 (Canadian counterpart, CA 1222697) discloses the suitability of partially etherified &bgr;-cyclodextrin and derivatives thereof, including hydroxyethyl, hydroxypropyl, and hydroxypropyl-methyl-&bgr; cyclodextrin for the solubilization of various types of drugs which are instable or only sparingly soluble in water. None of the drugs disclosed by EP 0149 197 B2 as having been solubilized with one or more of the partially etherified &bgr;-cyclodextrins was an antibiotic, much less an oxazolidinone. Likewise, U.S. Pat. No. 4,727,064 discloses the use of hydroxypropyl-&bgr;-cyclodextrin and the use of mixtures of that cyclodextrin derivative, diethylaminoethyl-&bgr;-cyclodextrin, carboxymethyl-&bgr;-cyclodextrin, and carboxamidomethyl-&bgr;-cyclodextrin to assist in the dissolution of drugs, but does not disclose the solibilization of any oxazolidinone using such a solubility enhancer. Various sulfoalkyl ether cyclodextrin derivatives, including sulfobulylether-&bgr;-cyclodextrin, and their utility in solubilizing certain active agents are disclosed in U.S. Pat. Nos. 5,134,127; 5,376,645. Uses of such sulfoalkyl ether cyclodextrin derivatives in solubilizing additional active agents are disclosed in U.S. Pat. Nos. 5,134,127, 5,874,418; 6,046,177; and 6,133,248.
Multi-dose formulations, including op
Adams Lisa A.
Bandyopadhyay Paramita
Hasan Syed
Hawley Leslie C.
Sims Sandra M.
Ashbrook Charles W.
King Karen B.
Pharmacia Corporation
Reamer James H.
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