WO1996037191A1

WO1996037191A1 - Antibacterial compositions

Info

Publication number: WO1996037191A1
Application number: PCT/US1995/006587
Authority: WO
Inventors: Yusuf Ali; Rajni Jani
Original assignee: Alcon Laboratories Inc
Current assignee: Alcon Vision LLC
Priority date: 1995-05-24
Filing date: 1995-05-24
Publication date: 1996-11-28
Anticipated expiration: 1997-11-24
Also published as: AU2762195A; AU705718B2; JP2944759B2; JPH09507679A

Abstract

Aqueous pharmaceutical compositions containing a synergistic combination of ciprofloxacin and a polystyrene sulfonic acid polymer are described, wherein the compositions are clear solutions which are comfortable and have sustained release. Methods for use of the compositions are also disclosed.

Description

ANTIBACTERIAL COMPOSITIONS

Field of the Invention

The present invention relates to pharmaceutical compositions comprising a synergistic combination of a quinolone, specifically ciprofloxacin, and a polystyrene sulfonic acid polymer.

Background of the Invention

Ciprofloxacin (Ciloxan™, Alcon Laboratories, Inc., Fort Worth, Texas, U.S.A.) is being used to treat ocular bacterial infections. However, because of the poor solubility of ciprofloxacin at physiological or higher pH, ciprofloxacin formulations were developed at acidic pHs. When these formulations are administered topically to the eye, they can be uncomfortable for some individuals.

Summary of the Invention

The present invention is directed to improved topical ophthalmic or otic compositions containing ciprofloxacin and a polystyrene sulfonic acid polymer. The compositions are formulated such that the solubility of ciprofloxacin at a higher pH is increased by the use of an ionic polymer (namely, polystyrene sulfonic acid polymer) which binds with the ciprofloxacin. The binding between the polymer and the ciprofloxacin additionally provides for both initial and continual comfort upon instillation in the eye, as there is less free drug to irritate the tissues of the eye. Another added benefit to the compositions of the present invention is that there is sustained release of the ciprofloxacin.

Detailed Description of the Invention

The pharmaceutical compositions of the present invention contain a synergistic combination of ciprofloxacin having antibacterial activity and a polystyrene sulfonic acid polymer, preferably at physiological or near- physiological pH. These compositions are especially useful in the eye, as the compositions are comfortable upon topical administration to the eye and provide for sustained release of ciprofloxacin.

The polystyrene sulfonic acid polymers (and their salts) which are used in the formulations of the present invention have the following formula:

wherein,

R = H or CH^ and

X = an integer such that the molecular weight of the polystyrene sulfonic acid polymer may vary from about 10,000 to 1.6 million. In the preferred polystyrene sulfonic acid of the above formula, R is H and the molecular weight is between about 500,000 and 1,000,000, preferably about 600,000. The polystyrene sulfonic acid polymers are used in the formulas of the present invention at a concentration less than about 8.0 percent by weight (wt%), preferably less than about 5.0 wt%. Ciprofloxacin, its preparation and use as an antimicrobial, are disclosed in U.S. Patent No. 4,670,444 (Grohe, et al.). The entire contents of that patent is incorporated herein by reference.

Ciprofloxacin has the following structure:

The chemical name for ciprofloxacin is l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- (l-piperazinyl)-3-quinoline carboxylic acid.

The ciprofloxacin concentration in the formulations is less than or about 1.0 wt% of the total composition, preferably between about 0.1 wt% and 0.75 wt%. The most preferred concentration is between about 0.2 and 0.4 wt%.

The compositions of the present invention are prepared by combining the ciprofloxacin with the polystyrene sulfonic acid polymer in aqueous media and adjusting the pH, if necessary. The compositions of the present invention may also include one or more ingredients conventionally found in ophthalmic or otic formulations, such as preservatives (e.g., benzalkonium chloride or thimerosal), viscosity-imparting agents (e.g., polyvinyl alcohol or hydroxypropylmethyl- cellulose), and toniάty agents (e.g., sodium chloride or mannitol). The compositions will also normally include buffering agents, such as phosphates and citrates, to maintain the pH within the range of physiological pH (pH between 6.0 and 7.5). Hydrochloric acid or sodium hydroxide will typically be used to adjust the pH of the resultant composition. The compositions are useful in treating ophthalmic and otic bacterial infections and are administered one to four times daily according to the discretion of a skilled clinician.

The following example is presented to illustrate the preferred formulation of this invention.

EXAMPLE

Ingredient Amount w/v%

Ciprofloxacin HC1, Monohydrate 0.35*

PSSA - 78-7063 (Available from 50 ml** National Starch)

Mannitol 4.4

Boric Acid 0.3

NaOH and/or HC1 to pH 6.70

Purified Water Q.S. to 100 ml

-equivalent to υ.j% as Dase **2% FSSA solution in water

COMPOUNDING PROCEDURE

Into an agitator-equipped compounding vessel, add approximately 50% of the batch volume of Purified Water at 20-30°C.

2. While maintaining moderate agitation, dissolve the PSSA.

3. Into an agitator-equipped compounding vessel, add approximately 30% of the batch volume of Purified Water at 20-30°C.

4. While maintaining moderate agitation, dissolve the following:

Mannitol

Boric Acid

Ciprofloxacin HC1, Monohydrate 5. Add the Ciprofloxacin solution from Step 4 to the PSSA Solution slowly with mixing (Note: A precipitate may form briefly, but should dissolve in a few minutes.)

6. Rinse the Ciprofloxacin compounding vessel and transfer lines with 10% of batch volume of cool Purified Water and add to the PSSA /Ciprofloxacin

Solution.

7. Check and record the pH. Adjust the pH to interim target of 6.50 using 6N NaOH solution or IN HC1 solution (requires approximately 800mL 6N NaOH per 100L of batch volume). (Note: NaOH must be added slowly.) 8. Q.S. to 100% total batch weight with room temperature Purified Water.

Mix until homogeneous.

9. Check and record the pH. Adjust the pH, if necessary, to 6.70 ± 0.1 using 6N NaOH solution or IN HC1 solution.

10. Filter solution through a 6μm or smaller polishing filter into the receiving reactor.

11. Sterilize the product in the reactor for a minimum of 30 minutes at a minimum of 121°C.

12. Cool the product to approximately room temperature with stirring by introducing cool water into the reactor jacket.

13. If batch weight is less than 99% of the weight measured in Step 10, adjust to the weight in Step 10 with Purified Water through the hydrophilic sterilizing filter. Mix to homogeneity (minimum of 15 minutes).

The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.

Claims

We Claim:

1. An aqueous composition useful in the treatment of bacterial infections which comprises a pharmaceutically effective amotmt of dprofloxadn and a polystyrene sulfonic add polymer.

2. The composition of Claim 1, wherein the dprofloxadn is present at a concentration less than or equal to about 1.0 wt%.

3. The composition of Claim 2, wherein the dprofloxadn is present at a concentration between about 0.1 wt% and 0.75 wt%.

4. The composition of Claim 3, wherein the dprofloxadn is present at a concentration between about 0.2 to about 0.4 wt%.

5. The composition of Claim 4, wherein the dprofloxadn is present at a concentration of about 0.3 wt%.

6. The composition of Claim 1, wherein the polystyrene sulfonic add polymer has the following formula:

wherein: R = H or CH^ and X = an integer such that the molecular weight of the polystyrene sulfonic add polymer may vary from about 10,000 to 1.6 million.

7. The composition of Claim 6, wherein the concentration of the polystyrene sulfonic add polymer is less than or equal to about 8.0 wt%.

8. The composition of Claim 6, wherein the concentration of the polystyrene sulfonic add polymer is less than or equal to about 5.0 wt%.

9. The composition of Claim 6, wherein R is H and the molecular weight is between about 500,000 and 1,000,000.

10. The composition of Claim 9, wherein the molecular weight is about 600,000.