Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-07-16
2002-10-08
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S255030, C424S449000
Reexamination Certificate
active
06462033
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to topically administrable ophthalmic and otic pharmaceutical compositions. In particular, this invention relates to a process for manufacturing compositions comprising ciprofloxacin, hydrocortisone and lecithin.
DESCRIPTION OF RELATED ART
U.S. Pat. No. 5,843,930 discloses topically administrable ophthalmic and otic compositions comprising (a) ciprofloxacin in aqueous solution in an amount effective for antibacterial action; (b) a non-ionic viscosity augmenter unaffected by pH and ionic level, said viscosity augmenter being present in an amount effective for augmenting the viscosity of the composition to a viscosity greater than that of water, said viscosity augmenter being at least 85% hydrolyzed polyvinyl alcohol; (c) a non-ototoxic preservative present in an amount effective for antibacterial action the preservative being benzyl alcohol; (d) water sufficient to produce an aqueous composition; (e) hydrocortisone in aqueous suspension in an amount effective for anti-inflammatory action; (f) lecithin in an amount effective for enhancing suspension of other constituents in the compositions; and (g) polysorbate ranging from polysorbate 20 to 80 in an amount effective for spreading the preparation on a hydrophobic skin surface to the site of infection or inflammation.
According to the '930 patent, the compositions comprising ciprofloxacin and hydrocortisone contain polyvinyl alcohol in an amount effective for augmenting the viscosity of the composition to a viscosity greater than that of water and suspending other constituents of the composition. To allow a ciprofloxacin preparation to be administered in drops from a medicine dropper and to flow by gravity to and remain or deposit in an effective amount at a selected area, a viscosity-augmenting agent that would also serve to suspend hydrocortisone was desirable. For compatibility with ciprofloxacin hydrochloride solubility, viscosity-augmenting agents were preferably non-ionic and unaffected by pH and ionic level. See Col., 8, lines 13-31 of the '930 patent.
Polyvinyl alcohol was selected for its ability to produce a suitable viscosity and a high ability to suspend hydrocortisone in aqueous preparations. See the '930 patent at Col. 8, lines 32-37. The addition of lecithin to the composition enhanced the efficacy of polyvinyl alcohol in suspending hydrocortisone in aqueous preparations with ciprofloxacin hydrochloride and other components. See the '930 patent at Col. 8, line 64-Col. 9, line 12.
The '930 patent discloses a process for manufacturing compositions containing ciprofloxacin and hydrocortisone in Example 5 at Column 5, lines 27-67. According this manufacturing process, polyvinyl alcohol, lecithin, benzyl alcohol and acetic acid are sequentially added to prepare a first stock solution. Separately sodium chloride and sodium acetate are dissolved in water to form a second stock solution. A third stock solution is prepared by dissolving polysorbate 20 and dispersing hydrocortisone in water. Finally, ciprofloxacin is either added to the first stock solution or ciprofloxacin is prepared as a fourth stock solution by dissolving ciprofloxacin, acetic acid and sodium acetate to form a ciprofloxacin stock solution. After the first and second stock solutions are combined, the ciprofloxacin stock solution is added to the combined solution. Finally, the third stock solution polysorbate 20 and hydrocortisone is mixed with the remaining batch volume.
A suspension composition's physical stability can be measured by two common methods. First, the resuspendability of a composition can be measured by allowing a homogeneous to remain standing in a cylindrical container for a period of time, then determining the number of inversions of the cylindrical container necessary to resuspend any sediment that form while the composition was standing. Second, the rate of settling can be measured by allowing a homogeneous suspension composition to remain standing for a period of time, then observing the height of sedimentation visible in a sample contained in a cylinder. Larger sedimentation heights indicate less separation with less supernatant liquid. Both measures of physical stability are important. A composition that is very easy to redisperse but that settles too quickly can be difficult to manufacture. Suspension compositions must remain well dispersed during processing and filling operations while commercial supplies are prepared in order to insure uniform products.
SUMMARY OF THE INVENTION
The present invention provides ciprofloxacin and hydrocortisone compositions that have excellent physical stability. The compositions are prepared by dispersing for greater than 45 minutes hydrocortisone with lecithin and optionally a polysorbate surfactant prior to combining hydrocortisone with the remainder of the composition. Among other factors, the present invention is based upon the finding that a specific order of addition of ingredients in compositions containing ciprofloxacin, hydrocortisone, a preservative, a non-ionic surfactant, a buffer, a tonicity agent, lecithin, polyvinyl alcohol and water can provide compositions with excellent physical stability. Compositions prepared by dispersing hydrocortisone with lecithin prior to mixing hydrocortisone with the balance of ingredients in the compositions have superior physical stability compared to those prepared by dispersing hydrocortisone with only a polysorbate surfactant prior to adding the hydrocortisone ingredient to the balance of the composition.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated, all ingredient concentrations are listed as percent (w/w).
Ciprofloxacin is present in the compositions of the invention in an amount effective for anti-bacterial action. Such amounts range from about 0.01-1%, preferably from about 0.1-0.5%, and most preferably about 0.2%. Compositions of the present invention also comprise hydrocortisone as an anti-inflammatory agent. Hydrocortisone is present in an amount effective for anti-inflammatory action. Such amount typically ranges from about 0.1-3%, preferably about 0.1-2%, and most preferably about 1%. Particularly for ophthalmic use, small particle sizes are preferred. As used herein, “micronized” hydrocortisone means hydrocortisone particles having an average particle size ≦10 &mgr;m (based on surface area (dsn)). If the particle size of the hydrocortisone raw material as received from the supplier is unsatisfactory, one or more known sizing techniques, such as ball milling or micronizing, can be used to adjust the particle size into the desired range.
To prevent contamination by microorganisms and provide a reasonable shelf-life, the compositions of the present invention include a preservative. Acceptable preservatives are required to cause no or insignificant ototoxicity, sensitization or irritation of the ear. Additionally, the preservative must be jointly soluble with ciprofloxacin in water over a pH range of approximately pH 3-6. The most preferred preservative is benzyl alcohol, which is typically present in an amount from about 0.1-3%, preferably about 0.1-2%, and most preferably about 0.9%.
A tonicity adjusting agent is preferably contained in an amount sufficient to cause the composition to be approximately isotonic, that is an amount effective to adjust the tonicity of the composition from about 150-800 mOsm, preferably 200-600 mOsm. A preferred tonicity-adjusting agent is sodium chloride.
A buffering agent is desirable for the compositions of the present invention. The preferred buffering system is an acetate buffer comprising acetic acid and sodium acetate. Amounts of sodium acetate and acetic acid effective to buffer the preparation in a pH range of about 4.0-5.3, preferably about 4.4-4.9 and most preferably about 4.7, range from about 0.1-3% of sodium acetate and from about 0.01-10% of acetic acid. Preferably the amount of sodium acetate is from about 0.1-2% and most preferably about 0.6-0.7%. Preferably the amount of sodium acid is ab
Alcon Universal Ltd.
Hui San-ming
Ryan Patrick M.
Travers Russell
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