Topical suspension formulations containing ciprofloxacin and dexamethasone

Topical suspension formulations containing ciprofloxacin and dexamethasone

dexamethasone

Full description

Background of the invention

This invention relates to formulations of ciprofloxacin and dexamethasone that are topically administrable in the eye and ear. The compositions according to the present invention are suspensions with excellent physical stability and are characterized by their resuspendibility in an easy and quick manner. More precisely, the invention relates to fixed suspension compositions of ciprofloxacin and dexamethasone lacking a nonionic tonicity agent, such as glycerol or mannitol.

Spanish patent application No. A1 2,065,846 (filed February 16, 1995) describes combination products of a steroid and an antibiotic that can be administered topically to the eye and ear. Examples 1-3 under this application show ophthalmic suspension formulations containing combinations of a particular drug with excipients including nonionic polymers and nonionic surfactants. Example 1 describes a combination of clobetasone and lomefloxacin containing an anionic tonic agent (glycrine). Example 2 describes a combination of fluoromethalone and norfloxacin containing an ionic tonic agent (sodium chloride). Example 3 describes a combination of ciprofloxacin and dexamethasone containing a deionized tonic agent (mannitol).

U.S. Patent Nos. 5,540,930 and 5,747,061 describe topical steroid suspension compositions containing an anionic polymer, an anionizable surfactant, and an anionizable tonic agent. These two patents relate to stable suspensions of water-insoluble steroid drugs with a particle size of less than or equal to 15 micrometer (μm). These suspensions remain in such a state until they are allowed to be immediately suspended, according to Desire, even after stability for extended periods of time (see summary of US Patent No. 5,747,061). The patents are based on the discovery that unexpectedly common stress agents, such as aqueous solutions containing 0.9% NaCl, 0.1% EDTA, and phosphate buffer, cannot be used even at concentrations as low as 1 mM ( mM)millimolar, to obtain stable aqueous suspensions of corticosteroids such as loteprednol etabonate (LE) (see US Patent No. 5,747,061, column 2, lines 52-56).

US Patent No. 5,747,061 refers to compositions meeting the need for "aqueous suspensions of corticosteroids such as LE, which can be prepared without agglomeration" (Column 2, lines 57-59). The compositions pursuant to U.S. Patent No. 5,747,061 contain (a) a soft steroid such as LE present in the form of particles preferably with a mean diameter less than about 15 microns, and (b) an anionic polymer as a suspending agent. , (c) non-ionizing surfactant and (d) non-ionizing surfactant. US Patent No. 5,747,061 defines a “soft” drug as a biologically active chemical component characterized by being convertible in vivo into non-toxic derivatives through a metabolic process that can be predicted in advance after administration. Its therapeutic effect. US Patent No

5,747,061 It is necessary for these components (a) to (d) to be as non-ionizing as possible because it has now been discovered that the presence of ions is a major cause of caking (column 3, lines 51-53). Nonionic diols such as glycerin or mannitol (as well as the commonly used sodium chloride) are known as the preferred stressors (see column 3, lines 53-56). It is preferable that the non-ionizing stress agent be present in an amount ranging from 0.5 to 10% by weight.

International Patent Application No. 0193390 describes a topical ophthalmic composition comprising dexamethasone, ciprofloxacin, edetate disodium, sodium chloride tyloxapol, hydroxyethyl cellulose, and benzalkonium chloride sulfur Sodium sulfate and acid Sulfuric

Sulfuric acid has a pH of 5.5 ± 0.5.

U.S. Patent No. 5-540,930 or A-5,747,061 describes fixed ophthalmic suspensions for use in the ears and throat of a corticosteroid such as loteprednol etabonate comprising a nonionic tonic agent such as mannitol or glycerol. General description of the invention

All ingredient amounts given in percentage form are represented in percentage units by weight unless otherwise stated.

The compositions of the present invention are compositions of aqueous suspensions of corticosteroids (dexamethasone) that avoid agglomeration. In addition to the corticosteroid, these formulations include an antibiotic (ciprofloxacin) as a second active agent. The compositions according to the present invention contain an ionic tensioning agent, but at the same time are stable so that they can be easily and instantly resuspended as desired.

Detailed description of the invention

The compositions according to the present invention include a corticosteroid and an antibiotic. The corticosteroid is dexamethasone and the antibiotic is ciprofloxacin. Dexamethasone can be found in any form that can be administered to the eye or ear and has poor water solubility such that the resulting formulation is a suspension. Suitable forms of dexamethasone include dexamethasone alcohol and dexamethasone acetate. Dexamethasone alcohol is the preferred form of dexamethasone. Ciprofloxacin exists in any form that can be administered into the eye or ear, with the ciprofloxacin component dissolved in the solution of the final formulation. Ciprofloxacin hydrochloride, monohydrate is the preferred form of ciprofloxacin.

The dexamethasone component should represent approximately 0.01-0.5% and the ciprofloxacin component should represent approximately 0.1-0.4% of the compositions according to the present invention. Preferably, dexamethasone and ciprofloxacin are present in the compositions according to the present invention in amounts of 0.1 and 0.3%, respectively.

In addition to the active agents, the compositions according to the present invention contain sodium chloride as an ionic tonic agent. The amount of NaCl depends on the desired tonicity of the final composition. But it generally ranges from 0.1-0.9%. For ophthalmic and otic uses, the suspension compositions according to the present invention preferably contain sufficient NaCl such that the compositions have an osmolality of about 350-250 milli osmol (mOsm).

The suspension formulations also contain an anionic polymer. Several deionized polymers are known that can be administered into the eye or into the ear. These include polymers

hydroxyethyl cellulose; hydroxypropylmethyl cellulose; methyl cellulose; carboxymethyl cellulose; Polyvinyl pyrrolidone and polyvinyl alcohol. Hydroxyethyl cellulose is the preferred deionization polymer. The deionized polymer is present in the compositions according to the present invention in an amount ranging from about 0.1-0.5%. In the case of hydroxyethyl cellulose, the preferred concentration of the deionized polymer is 0.2%.

The compositions according to the present invention also contain an anionic surfactant in an amount of about 0.01-0.2%. Several non-ionizing surfactants are known that can be administered in the eye and ear. Suitable anionic surfactants include tyloxapol; Polyoxyethylene sorbitan esters, such as polysorbate 20; polysorbate 60 60 polysorbate, and polysorbate 80 80 polysorbate; Polyethoxylated castor oils, such as EL cermaphor; polyethoxylated hydrogenated castor oils such as HCO-40; And poloxamers. Tyloxapol is the surfactant of choice.

The formulations may contain quaternary ammonium halide as a preservative as desired. Suitable quaternary ammonium halides include polyquaternium-l halides and benzalkonium. Preferred benzalkonium halides include benzalkonium chloride (BAC) and benzalkonium bromide. In general, the amount of the preserving ingredient ranges from about 0.005-0.3%. In the preferred case, where the preservative is BAC, it is preferable to have it at a concentration of

A chelating agent may also be present in the suspension compositions according to the present invention, if desired. Suitable chelating agents include edetate disodium (&EDTA; edetate trisodium; edetate tetrasodium; and diethylene amine pentaacetate. EDTA is the most preferred. The chelating agent, if present, is usually present in an amount of From about 0.001-0.1% and in the case of EDTA, the chelating agent is preferably present at a concentration of 0.01%.

In the case of preserved or multi-dose compositions, the suspension compositions according to the present invention may contain boric acid in an amount ranging from 0.1-1.5%.

The compositions according to the present invention have a pH ranging from 3-5, preferably 4.5. The pH can be adjusted using NaOH or HCl. The preferred buffer system for formulations is a combination of sodium acetate and acetic acid. The concentration of sodium acetate generally ranges from 0.01-0.06%, preferably about 0.03%, and the concentration of acetic acid generally ranges from 0.02-0.08, preferably about 0.04%.

The average particle size (based on the average volume value) of dexamethasone ingredient should be less than 10 micrometers to avoid irritation or discomfort. Preferably, the average particle size should be less than 6 micrometers, and most preferably less than 3 micrometers. Dexamethasone particle size can be determined using well-known techniques, such as ball-milling, microfluidization, and sonication.

The suspension compositions according to the present invention are intended to be administered topically in the eye, ear, or nose.

The following examples illustrate the present invention, but are not limited to them.

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Compositions A to E were prepared using the following method:

(1) A slurry was formed by mixing 75 grams (grams) of zirconium beads with an average size of 3 millimeters (mm), 12 grams of tyloxapol in a 1.0% stock solution, and 0.5 grams of dexamethasone alcohol. In a 30 ml polypropylene milling bottle (use approximately 48% of the final tyloxapol batch requirement to obtain a formulation batch size of 500 ml; (2) the slurry was steam sterilized (in an autoclave), Including That grits

beads;

(3) The sterile slurry was ground using a sterile grinding ball mill for 18 hours at a speed ranging from 50 to 55 revolutions per minute (rpm); (4) An aqueous solution was prepared containing the remaining tyloxapol requirement and the required amounts of all remaining ingredients. (For example, in the case of Formulation D, the remaining ingredients are ciprofloxacin hydrochloride monohydrate, benzalkonium chloride, sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose, boric acid, edetate disodium, and purified water); (5) Sterilize the aqueous solution prepared in step (4) with steam (in an autoclave); (6) The sterile slurry obtained in step (3) was mixed with the sterile solution obtained in step (5) by aseptically pouring the slurry through a sterile sieve (to remove granules) into the solution obtained in step (5);

(7) Adjust the weight of the formulation to 80-90% of the batch weight, using purified water obtained by sterile filtration;

(8) The final pH was checked and adjusted to a value of 4.5 ± 0.2 by adding sterile filtered sodium hydroxide or hydrochloric acid, as needed; And

(9) A sufficient amount of sterile filtered pure water was added until the weight of the formulation reached 100% of the batch weight.

An alternative method for preparing formulations A-H, especially when dexamethasone raw material is provided or is already available that meets the desired particle size specifications, is as follows:

(1) The raw dexamethasone material was sterilized by dry heating (according to the desired specifications: between 7-11 hours at an internal powder temperature of 130-140 °C);

(2) Prepare a solution of tyloxapol containing the batch requirement of tyloxapol in purified water;

(3) Sterilize the tyloxapol solution by passing it through a 0.2 µm filter;

(4) Mix sterile dexamethasone with sterile tyloxapol solution to form a sterile slurry and stir the mixture until it becomes homogeneous; (5) Prepare an aqueous solution containing the required amounts of the remaining ingredients (e.g., in the case of Formulation D, the remaining ingredients are ciprofloxacin hydrochloride, ciprofloxacin hydrochloride, chloride monohydrate

Benzalkonium chloride monohydrate, sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose, boric acid, edetate disodium,

and pure water);

(6) Sterilize the aqueous solution prepared in step (5) with steam (in an autoclave);

(7) The sterile slurry prepared in step (4) was mixed aseptically with the sterile solution prepared in step (6);

(8) Adjust the weight of the formulation to 80-90% of the batch weight using purified water obtained by sterile filtration;

(9) The final pH was checked and adjusted to a value of 4.5 ± 0.2 using sterile filtered sodium hydroxide or hydrochloric acid as needed; And

(10) A sufficient amount of sterile filtered pure water was added until the weight of the formulation reached 100% of the batch weight. Example 2

Compositions A-E were examined to determine the resuspension time in studies related to accelerated settling and real-time sedimentation.

real-time&amp;.

Accelerated sedimentation studies were conducted by subjecting 5 g of each composition, placed in a separate flat-bottom glass tube with dimensions of 16 x 125 mm, to centrifugation for 30 minutes at a speed of 3100 revolutions per minute using an IEC CENTRA-7 centrifuge. . The resuspendability of the precipitate was examined by measuring the seconds of wrist shaking required to completely resuspend the precipitate.

Real-time sedimentation studies were performed by allowing 5 g of each formulation placed in 16 x 125 mm flat-bottomed glass tubes to settle naturally (by gravity) for 7 days (except for formulation B, which was examined after 4 days). The ability to resuspend the precipitate was checked by measuring the number of inversions required to completely resuspend the precipitate. Table 2 includes resuspensibility results for the tested formulations.

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● Formulation B was examined after stabilization for 4 days; The other formulations were examined after 7 days. Example 3

Preservative Effectiveness Test:

The effectiveness of a preservative of a polymeric combination of a quaternary ammonium compound and boric acid according to the present invention against antimicrobial bacteria was determined by using an organism challenge test.

According to the methods described in the United States Pharmacopeia (USP) and the European Pharmacopeia (Ph.Eur.). The samples were inoculated with known levels of gram-positive vegetative bacteria (such as Staphylococcus aureus, according to the American Standard Culture Collection No. 6538) and gram-negative bacteria (such as Pseudomonas aeruginosa), according to to US Type Culture Kit No. 9027, Escherichia coli according to US Type Culture Kit No. 8739), and yeast (such as Candida albicans Candida albicans (US Standard Culture Kit 10231) and molds (such as Aspergillus niger) and samples were tested at specified intervals to determine whether the antibacterial preservative system was capable of eliminating Or intentionally inhibit the growth of organisms added to the formulation. The rate or level of antibacterial activity was determined according to the preservative effectiveness standards of the USP and/or Ph.Eur. that relate to ophthalmic preparations.

The requirements for preservative standards for ophthalmic preparations are summarized below:

For bacteria: (Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli)

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NI* = No increase at these elapsed times or at any subsequent elapsed times. NR** = No organisms recovered. - = There are no requirements at this elapsed time.

Table 3 shows the preservative resistance performed on the combinations of examples 1-4. These results demonstrate that, if desired, the suspension composition can be preserved in accordance with the present invention such that it meets the minimum preservative requirements of the United States Pharmacopeia (USP) and the US Pharmacopeia.

European Medicines (Ph.Eur) for ophthalmic and ear formulations.

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It is noted from Table 3 that all the formulations presented in the table passed the preservation standards according to Ph.Eur.A against bacteria and Candida albicans, while formulations without boric acid had difficulty passing the preservation standards according to Ph.Eur.B against Aspergillus nigricans.

The combination of boric acid and benzalkonium chloride improved the effectiveness of the preservative against Aspergillus nigricans.

The formulation met the criteria for preservative effectiveness according to Ph.Eur.B. Formula B (without boric acid) only met USP standards and failed the minimum preservation requirement test for Ph.Eur. Formula C (without boric acid) met USP and Ph.Eur.B (minimum) requirements. Formulation A initially met Ph.Eur.B requirements, but showed diminishing efficacy against Aspergillus niger when retested after 52 weeks. Table 4 shows the initial results and after 52 weeks for Formula A.

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He describes the invention with reference to certain preferred embodiments; However, it should be realized that it can be embodied in other specific images or forms without deviating from its principle or essential characteristics. Therefore, the embodiments described above are considered to explain the invention in all respects and are not specific to it, provided that the scope of the invention is determined by the attached protection elements and not by the previous description.