Ophthalmic micellar compositions with enhanced stability

Medicilon has extensive experience of performing stability studies on active pharmaceutical ingredients, early prototype formulations and finished dosage forms. Stability testing is performed according to FDA-ICH guidelines, client approved protocols and standard operating procedures. Email:marketing@medicilon.com.cn web:www.medicilon.com

This invention relates to micellar compositions comprising at least one pharmaceutically active substance and a mixture of n-alkyl dimethyl benzyl ammonium chlorides, wherein the mixture comprises more than 30% n-alkyl dimethyl benzyl ammonium chlorides having a chain length superior or equal to C16, wherein the pharmaceutically active substance exhibits an improved stability. In particular, a composition is provided that comprises cetalkonium chloride micelles incorporating the prostaglanding-like therapeutic agent, latanoprost. This invention also relates to ophthalmic compositions containing such micellar compositions and methods of using these ophthalmic compositions for the treatment of eye conditions.

Prostaglandins suitable for use in the practice of the present invention may be prostaglandin D2 analogs, prostaglandin E2 analogs, prostaglandin F2α analogs, or any combination thereof. The present invention is of particular interest for prostaglandin F2α analogs. Thus, in certain embodiments, compositions of the present invention comprise at least one prostaglandin F2α analog such as, for example, latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2, or any combination thereof.

In certain embodiments, latanoprost is the only pharmaceutically active substance in a micellar composition of the present invention. In other embodiments, latanoprost is present in combination with at least one additional prostaglandin, for example a prostaglandin E2 analog such as unoprostone isopropyl, travoprost, bimatoprost, tafluprost, or 8-isoprostaglandin E2. Alternatively or additionally, latanoprost may be present in combination with at least one additional pharmaceutically active substance such as those described herein.

The amount of prostaglandins present in a micellar composition of the present invention will depend on the nature of the prostaglandin(s) and the intended use of the micellar composition, as well as on the size of micelles. In certain embodiments, the amount of prostaglandin or mixture thereof is comprised between about 0.001% and about 1% w/w, preferably between about 0.002% and about 0.1% w/w, and even more preferably between about 0.002% and about 0.01% w/w.

In certain embodiments, a pharmaceutically active substance comprised in a micellar composition of the present invention is “stabilized”. As used in the context of the present invention, the term “stabilized” means that in an inventive micellar composition, the pharmaceutically active substance exhibits an “enhanced stability”, “improved stability” or “increased stability” compared to its stability in currently available formulations for ophthalmic topical administration, in particular formulations that comprise BAK. Without being bound by any theory, it is believed that since the pharmaceutically active substance is solubilised in the micelle core, it is less available to contact with agents enhancing its degradation. “Stability” is defined as the extent to which a product retains, within specified limits and throughout its period of storage and use (i.e., its shelf life), the same properties and characteristics that it possessed at the time of manufacture. One of the purposes of stability testing is to provide evidence on how the quality of a drug substance or drug product varies overtime under the influence of a variety of environmental factors such as temperature, humidity and light. The results of such testing enable recommended storage conditions, re-test periods, and shelf lives to be established.

Although real-time stability studies include an evaluation of those factors that ultimately affect the expiration date of drugs, they are time- and cost-consuming. Conventionally, accelerated stability studies are used for predicting the shelf life of pharmaceutical products. Such accelerated studies generally submit the systems tested to a temperature of 40° C. for 6 or 9 months.

In certain embodiments, a micellar composition of a pharmaceutically active substance according to the present invention is stable for more than about 1 year, preferably more than about 2 years, most preferably more than about 3 years, when stored at room temperature.

Pharmaceutically active substances that are known to be unstable under storage conditions may be found in a wide variety of families of drugs, including those described above. In certain embodiments, such unstable pharmaceutically active substances are selected among prostaglandins, for example, prostaglandin F2, analogs, e.g., latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2, derivatives thereof, or any combinations thereof. In certain preferred embodiments, the pharmaceutically active substance is latanoprost, which has been shown to be unstable, for example, when formulated in benzalkonium chloride micelles.