EP0362277A1 - Preservative free ophthalmic ointments - Google Patents

Abstract

Opthalmic ointments not requiring preservatives can be prepared with 0.01-0.9% (by weight) of salts.

Description

PRESERVATIVE FREE OPHTHALMIC OINTMENTS

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Ophthalmic ointments roust meet certain U.S. preservative efficacy testing standards in order to be marketed. Classically, ophthalmic ointment preservation has been achieved by organic-based chemical preservatives such as chlorobutanol, methylparaben and propylparaben. However, many organic preservatives irritate ocular tissu and are discomforting. Thus it is desirable to be able t preserve ophthalmic formulations by some other means.

Single use dose, unit dose, have been developed by numerous purveyors of ophthalmic formulations which are sterilized by non-chemical means, autoclaving or sterile filtration. These single use products do not require preservatives because a fresh sterile unit is used at eac dosing interval avoiding potential microbial contamination. However, multiple use formulations are still faced with sterility problems because each use can introduce contaminates, microbes, onto the delivery devic which can then be transfered back into the container.

Ointments by nature are not particularly susciptable to single dose packaging because of the difficulty in expressing material from such a small package. Ointment materials are inherently not self-preserving so some preservative means is needed to meet most health agency preservative standards. ^""

It has now been found that adding low levels of a salt preserves ointments as measured against United States Pharmacopeia Preservative Efficacy Testing standards (USP PET). High salt concentration ophthalmic ointments are known (5% sodium chloride formulations) . For example, a hypertonic ointment of sodium chloride 5% in a base of mineral oil, lanolin, white petrolatum and water is marketed by Muro Pharmaceuticals, Inc. A similar sodium chloride 5% ointment is also produced by Akorn, Inc. This high level of salt in these ointments is used to provide temporary relief of corneal swelling or edema by dehydrating the tissue. So though these ointments are non-preserved, no one has previously determined that low levels of salt could be used to effect preservation of ointments.

Salts at low concentrations are non-irritating and non-discomforting. Nor do they cause adverse reaction which is particularly useful for ocular preparations. It has now been found that using between about 0.01% and 0.9% (w/w) salt in ointments provides a composition which meets USP PET standards and does not involve a chemical preservative which may be irritating or discomforting to ocular tissue. Such means for preserving ointments is particularly useful for ophthalmic ointments where the greatest likelyhood of reaction to organic preservatives is encountered.

Summary of the Invention This invention relates to an improved ointment which does not require use of an organic preservative, particularly an ophthalmic ointment, wherein the improvement comprises adding 0.01%-0.9% weight/weight of a pharmaceutically acceptable inorganic salt to an ointment formulation.

In a second aspect, this invention relates to a method for preparing preservative free ointments which method comprises adding between 0.01%-0.9% w/w of a pharmaceutically acceptable inorganic salt to an ointment formulation. A pharmaceutically acceptable inorganic salt is any salt derived from the reaction of an inorganic acid and base, which at the concentrations recited herein does not have deleterious or untoward effect when administered to mammal. Preferred salts are those derived from lithium, sodium, potassium, calcium, magnesium, or iron (the cation) and chloride, bromide, iodide, sulfate, carbonate and phosphate in its various forms (anions). Borate salt may also be used. Particularly preferred salts are sodiu - chloride, potassium chloride, calcium chloride, magnesium chloride, sodium or potassium salts of phosphates and sulfates, calcium sulfate, magnesium sulfate and sodium o potassium carbonate.

Salt concentrations may vary between 0.1 and 0.9% by weight. Concentrations between 0.05 and 0.3% are preferred.

It is intended that this invention be applied to all ointments, i.e., semi-solid preparations for external application to the body. The broad definition of an ointment and ointment bases by Remington's Pharmaceutical Sciences, published by the Mack Publishing Company of Easton, Pennsylvania, U.S.A., provides an extended discussion of ointmer.t bases and ointment preparations. This treatise breaks ointment bases down into four groups, oleaginous ointment bases, emulsifiable ointment bases, emulsion ointment bases and water soluble ointment bases. This invention can be used with each of these different classification of ointment bases, provided that water is not a primary constituent of the base (about 5% w/w or less).

Salts may be introduced into ointment bases by any means so long as a intimate and even distribution of the salt is effected. Salt, in powder form, or in a concentrated aqueous solution are the two primary forms -Δ-

for introducing salts into ointments.

It is anticipated that this method of preserving ointments can be used with drug containing ointments as well as those that are non-medicated.

The following examples are given to illustrate the invention, but not to limits its scope or application.

Esarople 1 Five ointment samples were prepared containing a range of sodium chloride concentration. The formulation is as follows:

Ingredient Percent (w/w) White Petrolatum USP QS

Mineral Oil USP 41.5

Petrolatum and Lanolin Alcohol 2

Salt See below

To this basic formulation was added sufficient sodium chloride (USP) to give the following salt concentrations: 0, 0.01, 0.03, 0.10, 0.20, 0.30% by weight/weight. QS means quantity sufficient to make 100% weight/weight. All formulations except the control, no salt, passed USP PET.

Claims

WHAT IS CLAIMED IS:

1. An improved ointment which does not require use of an organic preservative, particularly an ophthalmic ointment, wherein the improvement comprises adding 0.01%-0.9% weight/weight of a pharmaceutically acceptabl inorganic salt to an ointment formulation.

2. An ophthalmic ointment according to claim 1.

3. An ointment of claim 2 where the salt concentration is 0.05-0.3% w/w.

4. A method for preparing preservative free ointments which method comprises adding between 0.01%-0. w/w of a pharmaceutically acceptable inorganic salt to a ointment formulation.

5. An ophthalmic ointment prepared according to claim 4.

6. An ointment prepared according to claim 5 where the salt concentration is 0.05-0.3% w/w.