MXPA98010124A - Procedure to treat ocular infections with azitromic - Google Patents

Abstract

The present invention relates to methods and compositions for treating ocular infections. The method comprises administering topically, over the eye of an animal in need of such treatment, an amount of azithromycin to treat an occult infection.

Description

PROCEDURE TO TREAT OCULAR INFECTIONS WITH AZITROMYCIN FIELD OF THE INVENTION This invention relates to methods for treating ocular infections by topical administration of azithromycin over that of an animal in need of such treatment.

BACKGROUND OF THE INVENTION Azithromycin is the generic name (USAN) of 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antimicrobial compound derived from erythromycin A. Azithromycin is described in United States Patent No. No. 4,474,768 to Bright and U.S. Patent No. 4,517,359 to Kobrehel et al. These patents describe that azithromycin and certain derivatives thereof possess antibacterial properties and, therefore, are useful as antibiotics. Azithromycin is usually administered orally, in a series of different dosage forms such as tablets, capsules and suspensions, for the treatment of bacterial infections. However, until the present invention, azithromycin was not known to be effective when administered topically on the eyes. It is known that azithromycin is effective for the treatment of ocular infections in humans when it is administered systemically, for example, orally. However, it is also known that antibiotics that are effective when administered by a systemic route, are not necessarily effective when applied topically, directly on the eye. For example, it has been described that when tetracyclines are applied to the cornea, they do not penetrate through the intact normal cornea, although these can diffuse into the spinal fluid and ocular fluids if the systemic dose is sufficiently high (MG Douvas, et al. , Arch Opthalmol, 46:57, 1951).

BRIEF DESCRIPTION OF THE INVENTION This invention provides a method for treating an ocular infection, comprising administering topically, on the eye of an animal, including a human, in need of such treatment, an amount of azithromycin to treat an infection. Topical administration means the application, directly on the surface of the eye, of azithromycin in a composition comprising azithromycin and a pharmaceutically acceptable topical carrier. In a preferred embodiment, the composition is applied directly to the eye in the form of a single dose (equivalent to about 5 mg) per day for five days. It will be appreciated that a "single dose" means the amount for a single eye.

The invention further provides pharmaceutical compositions for direct topical application to the eye of an animal, including a human being, said composition being suitable for the treatment of an ocular infection, comprising azithromycin and a pharmaceutical carrier suitable for topical application, said azithromycin at a concentration in said vehicle sufficient to remedy said ocular infection. In a preferred embodiment, the concentration of azithromycin in the vehicle is such that a single dose (approximately 5 mg per eye) of said composition administered once a day for five days remedies the infection. The ability to achieve topical dosing once daily with azithromycin was quite unexpected considering that most drugs are rapidly eliminated from the precorneal area by the lacrimal drainage. Thus, the most common topical dosing guidelines that use antibiotics known as gentamicin and erythromycin should be administered frequently, with application guidelines of 4-6 times per day being necessary to produce effective drug levels in the target ocular tissues. Topical formulations of azithromycin, on the other hand, achieve relatively high and sustained levels in ocular tissues including the cornea, conjunctiva, eyelids and sclera. Due to the excellent penetration of azithromycin into ocular tissues, it can be expected that patient compliance will improve significantly by virtue of this invention.

The types of ocular infections that can be treated by the topical application of azithromycin generally include any infection caused by a known bacterial species that is susceptible to systemic treatment with azithromycin. In particular, the invention is applicable to the treatment of trachoma, a chronic follicular conjunctivitis caused by Chlamydia trachomatis, the world's leading cause of avoidable blindness.

• DETAILED DESCRIPTION OF THE INVENTION The term "azithromycin" includes the pharmaceutically acceptable salts thereof, and the anhydrous and hydrated forms. Azithromycin is preferably present in the dihydrate form, described, for example, in published European patent application 0.298.650-A2, and in the United States Application 07 / 994,040, being filed with the present, filed on 21 December 1992, which are incorporated herein by reference. The compositions (sometimes referred to herein as "formulations") according to the invention comprise azithromycin (calculated using the dihydrate) is present in the composition, typically at a concentration of 0.1 to 2.5% by weight (w / w) , usually from 0.2 to 2.0% by weight, based on the weight of the composition. A preferred concentration is 0.5% by weight.

If desired, the compositions may include a preservative, although the preferred compositions do not contain any preservatives. The compositions may further contain surfactants, viscosity enhancers, buffers, sodium chloride and water, to form sterile aqueous ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic ointment formulations, azithromycin is combined with a suitable vehicle such as mineral oil, liquid lanolin or white petrolatum. Sterile ophthalmic gel formulations containing azithromycin can be prepared by suspending azithromycin in a hydrophilic base prepared from a combination of, for example, a carboxyvinyl polymer marketed under the name Carbopol (registered trademark of BF Goodrich Company for a series of such polymers) according to published formulations for analogous ophthalmic preparations. Tonicity agents can also be incorporated into said gel formulations. Azithromycin can be formulated as an ophthalmic solution in isotonic saline using glycerin as an isotonicity agent. As the excipient, a preservative may optionally be included. Such ophthalmic solutions further include a pharmaceutically acceptable buffering agent, typically a combination of boric acid and sodium borate, sufficient to maintain the pH in the solution of 7 to 8. A preferred composition is 0.5% azithromycin dihydrate w / w suspended in a vehicle free of preservative, inert and non-allergenic, composed of white petrolatum (55% w / w), mineral oil (42.5% w / w) and lanolin (2% w / w). The invention is further described by means of the following non-limiting examples. In the examples, the reference to "water" refers to sterile water, suitable for use as water for injection.

EXAMPLE 1 A preferred embodiment was prepared by incorporating 5 g of azithromycin dihydrate into 995 g of a sterile vehicle composed of 55% by weight of white petrolatum, 43% by weight of light mineral oil and 2% by weight of lanolin. The method involves first heating an excess amount of the ointment vehicle of the aforementioned composition to 70 ° C in a glass container producing a melt. In the next step, 995 g of sterile molten ointment is transferred to a mixing vessel equipped with a mixer and 5 g of azithromycin hydrate are added to the mixture under stirring at 70 ° C, forming a suspension. The ointment containing azithromycin was quickly cooled by placing the mixing vessel in an ice bath. The "0.5% azithromycin ointment" is then filled into 1 cm3 plastic syringes of unit dose for the application of the dose. This ointment can be sterilized by gamma radiation using a source of cobalt 60.

EXAMPLE 2 An ophthalmic solution of azithromycin dihydrate at 0.5 percent by weight is prepared by dissolving 50 g of azithromycin dihydrate, (0.5% by weight), 67.0 g (0.67 percent by weight) of boric acid, 20.7 (0.207 percent by weight) of sodium borate decahydrate, 100 g (1.0 weight percent) of glycerin, 100 g of polyethylene glycol 300 (1.0 weight percent) and 0.40 (0.004 weight percent) of thimerosal (as a preservative) in about 8000 g of distilled water deionized. The pH is adjusted to 7.2 with HCl and NaOH. The weight of the final load is brought to 10,000 g with the addition of the necessary amount of water. The final solution is filtered through a 0.2 micron Millipore filter and filled into vials.

EXAMPLE 3 In a preferred embodiment, an 0.5% by weight ophthalmic azithromycin dihydrate suspension is prepared as follows: 600 g of petrolatum is heated at 90 ° C for 2 hours in a coated 316 stainless steel vessel. The temperature is then reduced to 60 ° C. Light mineral oil, 350 g, is added to the vaseline under gentle agitation. The solution is passed through a synthetic glass filter. The azithromycin dihydrate, 5 g, is dispersed in the mineral oil / petrolatum solution under agitation to form a finely dispersed suspension. The suspension is cooled under slow stirring forming a semi-solid suspension. The suspension is filled into polypropylene plastic tubes and sterilized by gamma radiation using a source of cobalt 60.

EXAMPLE 4 An 0.5% by weight ophthalmic azithromycin dihydrate suspension is prepared as follows: 600 g of PGE 4000 is heated at 90 ° C for 2 hours in a coated 316 stainless steel vessel. The temperature is reduced to 60 ° C. PEG 400, 350 g, is added to the vaseline under gentle agitation. The solution is passed through a synthetic glass filter. The azithromycin dihydrate, 50 g is dispersed in the solution of PEG 4000 / PEG 400 under agitation, forming a finely dispersed suspension. The suspension is cooled under slow stirring forming a semi-solid suspension. The suspension is filled into polypropylene plastic tubes and sterilized by gamma radiation using a cobalt source EXAMPLE 5 The following gel was prepared under stringent aseptic conditions:% w / w Azithromycin dihydrate 3.50 Clorbutol BP 0.50 Carbopol® 934P 2.50 NaOH (4% solution w / v) 6.21 Water 87.29 Azithromycin dihydrate is dispersed in sterile, non-neutralized Carbopol in water containing chlorbutol BP in solution. A 4% w / v sodium hydroxide solution is then added with constant mixing to a final pH of 4-6.

EXAMPLE 6 The following ingredients are formed in a mixture:% w / w Azithromycin dihydrate 3.50 Clorbutol BP 0.50 Citric acid monohydrate 0.117 Sodium citrate dihydrate 0.112 1% sodium citrate solution c.s.p. Hydroxypropylmethylcellulose USP 2906 4000 cps (sterile) 3.80 Water remaining up to 100.00"ie buffers Citric acid, sodium citrate and chlorbutol BP are dissolved in 95% of the total water and the solution is sterilized. Azithromycin powder is dispersed in the solution room temperature using a high shear mixer Hydroxypropylmethylcellulose, previously sterilized, is dispersed in the suspension and then allowed to hydrate for a period of about 15 minutes.The pH is adjusted to 4-6 with a 1% solution of sodium citrate sterilized The gel is adjusted to the final weight with water and mixed homogeneously.

EXAMPLE 7 The following suspension is prepared, which gels in situ at body temperature. % p / p Azithromycin dihydrate 3.50 Benzalkonium chloride BP 0.02 Citric acid monohydrate 0.117 Sodium citrate dihydrate 0.112 Pluronic® F127 ** 19.00 Sodium citrate / citric acid solution c.s.p. Water remaining up to 100.00 Pluronic F127 is a polyoxyethylene-polyoxypropylene block copolymer of molecular weight approximately 11,500. Citric acid dissolves, sodium citrate and benzalkonium chloride in 98% of the total water. The Pluromc? F127 is dispersed in this solution and allowed to hydrate overnight. The preparation is then mixed homogeneously and adjusted to pH 4-6 with sodium citrate or citric acid solution, as needed. The solution is brought to 96.5% of the total weight and filtered to sterilize in a sterile package. Azithromycin is dispersed aseptically in the filtered solution using a high shear mixer.

EXAMPLE 8 The following gel is prepared under stringent aseptic conditions. % p / p Azithromycin dihydrate 3.50 Ethylene resin and maleic anhydride (EMA) type 91 (sterile) 0.80 Diluted ammonium hydroxide solution (NH-3 at q.75%) 4.40 Water 90.80 The EMA resin is dispersed in 50% of the total water, the diluted ammonium hydroxide solution is stirred and the mixture is heated at 95 ° C for 15 minutes. The resulting gel is allowed to cool to below 60 ° C. The chlorbutol BP is dissolved in the remaining 50% of water at a temperature not exceeding 60 ° C and filtered to sterilize in the gel which is slowly mixed. Azithromycin is dispersed homogeneously in the gel.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. The use of azithromycin in combination with a pharmaceutically acceptable topical vehicle in the manufacture of a composition for treating an eye infection in an animal.

2. The use according to claim 1, wherein the combination obtained with said azithromycin and said pharmaceutically acceptable topical carrier provides 0.1 to 2.5 weight percent, based on the weight of the azithromycin composition, to the eye of said mammal. per day ..

3. - A composition for direct topical application on the eye of an animal, including a human being, said composition being suitable for the treatment of an eye infection, comprising an effective amount of azithromycin in a pharmaceutical carrier suitable for topical application on the eye.

4. A composition according to claim 3, wherein said azithromycin is present in a range of 0.1 to 2.5% by weight.

5. A composition according to claim 3, wherein said azithromycin is present in an amount of 0.5% by weight.

6. A composition according to claim 3, wherein said composition is 0.5% w / w of azithromycin dihydrate suspended in a preservative-free, inert and non-allergic vehicle, comprising white petrolatum (55% w / w), oil mineral (42.5% w / w) and lanolin (2% w / w).