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Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses

Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses description/claims

This application claims the benefit of priority under 35 U.S.C. §119(e) to co-pending U.S. Provisional Application No. 60/899,176 filed Feb. 2, 2007, entitled “Non-Alcoholic Foamable Petrolatum Based Pharmaceutical And Cosmetic Compositions And Their Uses”, which is incorporated in its entirety by reference

This application claims the benefit of priority under 35 U.S.C. §119(e) to co-pending U.S. Provisional Application No. 60/915,859 filed May 3, 2007, entitled “Non-Aqueous Foamable Petrolatum And Miscible Solvent Based Pharmaceutical And Cosmetic Compositions And Their Uses”, which is incorporated in its entirety by reference.

This application is a continuation-in-part of co-pending U.S. patent application Ser. No. 11/940,290, filed on Nov. 14, 2007, which claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60/858,747, filed on Nov. 14, 2006, both entitled “Stable Non-Alcoholic Foamable Pharmaceutical Emulsion Compositions With An Unctuous Emollient And Their Uses”, and both herein incorporated in their entirety by reference.

Petrolatum is used in dermatology to lubricate, protect, heal and medicate the skin and as a vehicle for topical drugs. Petrolatum is not suited to formation of foams. It is an unctuous solid and does not flow and is not shakable per se. Addition of large amounts of propellant to try and improve its flow is not desirable in general since the resultant material can have a cooling effect on application to the skin, mucosal cavity or body cavity. Addition of hydrophobic solvents can be useful to improve healing qualities of the formulation and to soften the petrolatum, but it can also significantly and substantially complicate or impede foam formation.

Foams are complex multi-ingredient systems which do not form under all circumstances. High quality foams are not at all easy to produce especially in a waterless environment. Yet, foams are easy to apply, use and spread and are a preferred mode of topical application. Changes in foam composition, such as, by the addition of active ingredients, may destabilize the foam. There is, therefore, a need for a foam composition, which provides desirable properties to the skin or body cavity and can be stable whilst accommodating a variety of active ingredients.

Petrolatum in its various forms has a number of useful attributes for use in topical foamable pharmaceutical and cosmetic compositions. They are inherently stable and inert, which are clearly desirable characteristics. They are also able to moisturize and soften the skin and in appropriate amounts can act as a protective or barrier layer and can form a barrier to water, which can, for example, solubilize or cause destabilization of some active ingredients. By careful design and appropriate formulation of petrolatum compositions they can act to improve drug delivery to the skin; provide a protective environment for the drug and yet remain resistant to being washed off unintentially. On the other hand petrolatums are by their nature greasy materials and can present a difficult challenge to formulate them into a topical non-aqueous or substantially so foamable composition that can deliver substantially uniform and stable foam that ameliorates and or overcomes the look and feel of a greasy material. It is further a problem to incorporate into such a vehicle pharmaceutically effective amounts of one or more active pharmaceutical ingredients such that they are uniformly present throughout the formulation and are effectively delivered especially without the use of an alcohol in the formulation.

Aliphatic alcohols in foam compositions promote fast drying and thereby attempt to address the sticky feeling left by many topical formulations after application; however, alcohols, and in particular short chain alcohols like methyl, ethyl and isopropyl alcohols are defatting agents and may cause skin to become dry and cracked. Also, the presence of such alcohols generates alcoholic foam that is thermal sensitive and quick breaking, e.g., it collapses readily upon contact with a surface upon exposure to body temperature environment. Although certain compositions based on petrolatum are known they are, for example, designed to form an occlusive layer in the presence of active pharmaceutical agents that are not soluble in the water or oil phase. Although some lipophillic compositions containing petrolatum and silicone oil are known, the silicone oil is an essential and main component and it is used to try and overcome the greasy feeling of petrolatum. Silicones can have substantial disadvantages in foamable compositions and foams especially in significant levels.

In the light of the unctuous, greasy, tacky, and heavy nature of petrolatum, there are problems in producing stable emulsion foams of good quality and texture from high levels of petrolatum and there is a real technical challenge of achieving inter alia a good bubble structure, texture, spreadability and look and feel. The presence of water is important in contributing to feel of the foam. Developing foams with such characteristics that are substantially free of water is a technical and inventive challenge. This challenge is increased where the formulations are to be substantially free of silicone oil and substantially free of lower alcohols.

Alcohol is known to impair the integrity of the skin barrier, dry the skin and cause skin irritation. The incidence skin irritation (burning, itching and stinging) can be very high. Thus, while alcohol is useful in solubilizing an active agent and enabling effective dermal penetration of an active agent, the development of a safe foam vehicle, which will overcome the evident skin drying and irritation caused by alcohol, is warranted, especially where sensitive skin, mucosa, or body cavity membranes are being targeted. Furthermore, foam compositions that possess a lesser degree of thermal sensitivity, thus being more useful for the treatment of large skin areas are desired.

Foamable compositions that produce foams, which are soft are desirable especially with improved stability.

It is particularly advantageous to have a foamable vehicle that is suitable for use as a base for delivery of not merely one type of active pharmaceutical ingredient (API) but is adaptable for use with one or more API's from a wide range of different types of API's with relatively minimal or minor adjustment to the vehicle. For example, by altering the amount of a component or by the addition of a buffer that provides a pH at which the API is stable as would be appreciated by a person skilled in the art.

This application relates to petrolatum-based foamable vehicles, pharmaceutical compositions and resultant foams. In one embodiment, the petrolatum-based foamable vehicles, pharmaceutical compositions and resultant foams are non-aqueous. In one embodiment, petrolatum-based foamable vehicles, pharmaceutical compositions and resultant foams have low water content. The application further relates to such compositions and to such resultant foams that are non-silicone and or are non-alcoholic or substantially so.

A prime concept covered herein is that petrolatum as a hydrophobic carrier is a main ingredient and is at least about 50% of the foamable carrier alone or in combination with a solvent substantially miscible therein for example a hydrophobic oil. In a preferred aspect the percentage of petrolatum is more than about 60%. In one aspect the foamable carrier is non-aqueous and the petrolatum is at least about 25% and is in combination with a solvent substantially miscible therein such that together they are at least about 80% and the carrier is substantially free of silicone oil. By substantially free it is meant that the silicone oil content in the composition is less than about 1%. In another aspect the foamable carrier is substantially non-aqueous or has low water content and the petrolatum is more than about 50% or more than about 55% and preferably more than about 60%. By substantially non-aqueous or low water content it is meant that the amount of water if present in the composition is small and is less than about 26%, preferably less than about 16% and more preferably less than about 13%. Although the proportion of water is relatively very small by selective use of appropriate and compatible surfactants it can be possible to produce both water in oil and also oil in water petrolatum emulsion compositions. Whilst these carriers are intended to be without lower or short chain alcohols, where an API is provided as an alcoholic extract, such small amount of alcohol is permitted in the compositions. In certain embodiments, such lower alcohol content is reduced or essentially eliminated by evaporation upon warming.

In an embodiment the petrolatum based carriers comprise one or more active pharmaceutical ingredients (API's). The formulations are designed to carry homogeneously large ranges of API's from microgram levels to up to about 33% of the composition. Some API's are stable in one kind of environment whilst others require a different environment. For example, many steroids are known to undergo rearrangement at high pH, and are more stable in acidic formulations whilst vitamin D and its derivatives fare better in a basic medium. So adding an acidic modulating agent such as an acidic buffer, or fatty acid helps prevent steroid degradation whilst the addition of a basic modulating agent, such as a basic buffer or triethanolamine is useful to maintain acceptable stability for vitamin D and derivatives. Other substances break down or react more rapidly in the presence of water and therefore are sustained better in a non-aqueous medium. The formulations described herein offer waterless and substantially waterless or low water content variations and an appropriate carrier may be selected for an API depending on its sensitivity and reactivity in the presence and absence of relatively small amounts of water. Whilst the carrier compositions described herein may be useful carriers for API's some are not compatible in the same formulations and may react or breakdown. The formulations described are suitable for use in dual or multi chamber foam delivery devices, where each chamber delivers an API which if stored with the API's in the other chamber(s) would have broken down. In one embodiment the carrier in the first chamber is substantially waterless and the carrier in the second chamber is waterless. In another embodiment the carrier is basically the same in each chamber although some minor variations such as to pH or artificial pH or in the presence of one or more preservatives, stabilizers, antioxidants, and the like may be made to reflect the specific requirements of the API.

To generate the good quality foams described herein the formulations contain a foam agent. In one or more embodiments the foam agent is selected from the group consisting of a surfactant, a surfactant combination, a foam adjuvant and combinations thereof. In one or more further embodiments the quality may be improved by addition of a polymeric agent. The polymeric agent may preferably have some surfactant-like properties or help to ameliorate the tacky greasy properties of petrolatum.

In one embodiment, the foamable composition is a non-aqueous, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 25% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 70% by weight; and (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system, a foam adjuvant and combinations thereof; at a concentration of about 0.1% to about 20% by weight. In the absence of the solvent, the petrolatum is present in the foamable carrier at a concentration of at least about 50% by weight. In the presence of the solvent, (i) the petrolatum is present in the foamable carrier at a concentration of at least about 25% by weight and the solvent and petrolatum are together present in the foamable carrier at a concentration of least about 55% by weight; or (ii) the amount of petrolatum is about the same as or in excess of the solvent and, together, the solvent and petrolatum are present in the foamable carrier at a concentration of at least about 80%. The ratio of the foamable carrier to the propellant is 100:10 to 100:35. The composition is substantially free of silicone. The composition is stored in a pressurized container or aerosol container and upon release expands to form a breakable foam.

In one embodiment, the foamable composition is a non-aqueous, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 50% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 45% by weight; (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system; a foam adjuvant and combinations thereof at a concentration of about 0.1% to about 20% by weight; and (4) an effective amount of an active pharmaceutical agent. The ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35. The composition is substantially free of silicone. Moreover, the composition is resistant to centrifugation at 1000 rpm for about 10 minutes; is flowable or flowable to a degree and or is shakable or substantially so when stored in a pressurized container or an aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g.

In one embodiment, the foamable composition is a low water content, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 25% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of 0% to about 70% by weight; (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system, a foam adjuvant and combinations thereof; at a concentration of about 0.1% to about 20% by weight; and (4) water at a concentration of up to about 26% by weight. In the absence of the solvent, the petrolatum is present in the foamable carrier at a concentration of at least about 50% by weight. In the presence of the solvent: (i) the petrolatum is present in the foamable carrier at a concentration of at least about 25% by weight and the solvent and petrolatum are together present in the foamable carrier at a concentration of least about 55% by weight; or (ii) the amount of petrolatum is about the same as or in excess of the solvent and, together, the solvent and petrolatum are present in the foamable carrier at a concentration of at least about 80%. The ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35. The composition is substantially free of silicone. The composition is stored in a pressurized container or aerosol container and upon release expands to form a breakable foam. In one embodiment, the foamable composition is a low water content, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 50% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 45% by weight; (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system; a foam adjuvant and combinations thereof at a concentration of about 0.1% to about 20% by weight; and (4) an effective amount of an active pharmaceutical agent. The solvent is water and is present in the carrier at a concentration of about 0.1% to about 26% by weight. The ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35. The composition is substantially free of silicone. The composition is resistant to centrifugation at 1000 rpm for about 10 minutes and is flowable or flowable to a degree and or is shakable or substantially so when stored in a pressurized container or aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g

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