FIELD

This invention relates to waterless foam formulations, specifically single phase foamable composition including silicone. The invention further relates to methods for formulating stable and unstable active agents in topical compositions, which are suitable, inter alia, for applying to the skin or to mucosal surfaces and can be used for treating topical, mucosal and/or systemic disorders in mammals. The invention further relates to vehicles which are suitable, inter alia, for delivery for a wide range of active pharmaceutical and cosmetic agents and methods for their use.

BACKGROUND

External topical administration is an important route for the administration of drugs in both systemic and topical disease treatment. For example, diseases of the skin, such as inflammatory diseases (e.g., acne), rashes, infection (e.g., microbial infection and parasitic infestation), and immune system reactions leading to rashes and/or infection, are typically treated via topical administration of a pharmaceutical active agent. Many drugs that may be useful for topical administration (e.g., antibiotics, anti-fungal agents, anti-inflammatory agents, anesthetics, analgesics, anti-allergic agents, corticosteroids, retinoids and anti-proliferative medications) are preferably administered in hydrophobic media, such as a petrolatum-based ointment or a cream, due to their increased stability in hydrophobic solvents. While the use of stabilizers, anti oxidants antimicrobial preservatives, buffers and the like in aqueous compositions to protect active or cosmetic agents is known, there are still disadvantages to formulating certain active agents in aqueous compositions, or even in compositions containing low amounts of polar solvents such as water (e.g., water in oil emulsions). For example, some active agents are known to be generally unstable or susceptible to isomerisation or to breakdown in the presence of water, resulting in loss of activity. Thus, in several cases, many drugs are more soluble or more stable in hydrophobic solvents; and therefore, the development of simple and elegant formulations to accommodate and stabilize active ingredients in a hydrophobic waterless or substantially waterless environment is desirable.

However, hydrophobic formulations, in particular ointments, also pose disadvantages to topical administration. For example, ointments often form an impermeable barrier. In the treatment of a topical wound, such a barrier would prevent the removal or draining of metabolic products and excreta from these wounds. Moreover, the efficacy of drugs formulated in ointments is compromised because of the difficulty for an active drug dissolved in an ointment-based carrier to pass through the barrier layer into the wound tissue. In addition, ointments and creams often do not create an environment for promoting respiration of wound tissue or normal respiration of the skin. An additional disadvantage of ointment formulations is the greasy feeling left following their topical application onto the skin, mucosal membranes and wounds.

Formulations based on hydrophobic media also include those based on oils or hydrophobic emollient vehicles. These formulations have a number of useful attributes making them suitable candidates for topical pharmaceutical and cosmetic compositions, including foamable compositions. They are inherently stable and inert which are clearly desirable characteristics. They are able to condition the skin and in appropriate amounts can form a barrier to skin moisture loss. By appropriate formulation they can act to improve drug delivery to the skin and yet remain resistant to being washed off. On the other hand, they are by their nature greasy materials and can be difficult to formulate particularly into a topical foamable composition that can deliver a substantially uniform and stable composition or foam that ameliorates or overcomes the look and feel of a greasy material, especially where that composition is waterless or substantially so. 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 without the use of an alcohol in the formulation.

Foamable compositions offer advantages over ointments and creams for topical administration of pharmaceuticals. While hydrophobic foamable compositions are known, it is far from simple or obvious to produce hydrophobic waterless foamable compositions that when released produce foams of quality suitable for pharmaceutical or cosmetic application. On a further level, having realized a carrier that will produce a hydrophobic waterless foam of quality there is an additional difficulty to be overcome, namely how to adapt the formula and achieve a uniform formulation, which can accept a range of various active pharmaceutical and cosmetic agents such that the composition and active agent are stable and the foam produced remains of quality. Specifically, one of the challenges in preparing such waterless or substantially waterless foamable compositions is ensuring that the active pharmaceutical or therapeutic agent does not react, isomerize or otherwise break down to any significant extent during is storage and use. Particularly, there remains an unmet need for improved, easy to use, stable and non-irritating foam formulations, with unique therapeutic or beneficial properties containing a stable or stabilized active pharmaceutical or cosmetic agent.

Silicones are hydrophobic substances that offer unique cosmetic properties. They are tasteless, essentially odorless, non-greasy and non-stinging; they are used as a base fluid in many personal care products, with excellent spreading and easy rubout and lubrication properties. Volatile silicone compounds are a specific class of silicones, used in dermal formulations to condition the skin, while reducing the greasy feel of other oils in the formulation. However, one of the principal hindrances to the use of silicones in foam formulations is their known antifoaming effect, especially when included in the formulation in substantial quantities. More specifically, silicones are known for being efficient foam control agents and can prevent foam formation or cause foam to collapse rapidly. Silicone fluids can, for example, enter into the foam lamella and displace the foam stabilizing surfactants from the interphase. The foam lamellas are therefore destabilized and burst resulting in foam collapse. Thus, silicones are essentially contra-indicated for the preparation of foamable carriers and compositions. Nevertheless, because of the favorable properties of silicones, there is still an unmet need to develop foamable formulations incorporating silicone that can produce easy to use good quality foam, especially in substantial quantities.

In general terms foam formed from hydrophobic waterless or substantially waterless compositions may by their inherent nature be less firm or inherently weaker than water based emulsion compositions. Thus, not only are silicones inherently unsuitable for forming foamable compositions but it may additionally go against the grain to try and use them in waterless compositions.

US Patent Publication No. 2008/0031908 describes an aerosol product containing an oily composition containing at least one oil, and at least one hydrocarbon compound (notably, a paraffin or a fatty acid amide) having a melting point greater than or equal to 30° C. (i.e., a solid at room temperature), the compound being in the form of solid particles and one or more propellants. Hydrocarbon solid particles were required to provide a fine bubble, stable foam.

US Patent Publication No. 2005/0287081 (corresponding to International Patent Publication No. WO 2006/031271) describes a topical pharmaceutical aerosol foam containing high levels of liquid silicones to enhance cosmetic elegance, containing five essential ingredients: (1) a lipophilic compound or combinations of lipophilic compounds; (2) a liquid silicone or a combination of liquid silicones; (3) a foaming agent, which is selected from the group consisting of mono, di, tri esters of sorbitol and fatty acids; (4) an active agent; and (5) a propellant. The formulations described in the publication contain less than 60% liquid oil and significant levels of liquid silicone, indicating that foamable compositions containing very high levels of liquid oil were not achieved. Notably, the foam product of the formulations described in US 2005/0287081 is prone to collapse quickly as illustrated below in the Examples, which is also undesirable for a topical foam formulation.

U.S. Pat. No. 3,770,648 teaches that solid silicone resin must be present in quantities to produce a quick breaking anhydrous foam.

Foams are complex dispersion systems which do not form under all circumstances. Slight shifts in foam composition, such as by the addition of active ingredients, may destabilize the foam. Foams are very complex and sensitive systems and are not formed at will. Mere addition of basic ingredients like oil, surfactant and propellant is far from sufficient to produce foams of quality that are homogenous, stable, breakable upon mechanical force and can be used to provide a shelf stable pharmaceutical or cosmetic composition. Small deviations may lead to foam collapse. Much consideration needs to be given to facilitate the introduction of an active agent, such as examining compatibility and non reactivity with the various excipients and container and determining shelf life chemical stability.

Neubourg (US 2006/0099151), for example, notes that the stability of foam is strongly dependent on the specific composition of the foam forming components, so that even small deviations in the composition may lead to a collapse of the foam. Gordon et al. (U.S. Pat. No. 3,456,052). also teaches that one cannot generate a good quality foam by simply adding a propellant to a mixture of components:

The term “foam” is a general term that encompasses a range of substances. Accordingly, the context in which “foam” is discussed must be examined carefully. The type and quality of the foam is of critical importance. There are many different types of foams and within each foam type there are many levels of qualities. For example, the froth on the head of beer, lather of shampoo, and lather of shaving cream have been loosely described as foam but all are different from one another. At one end of the cosmetic or pharmaceutical foam spectrum the foam can be long lasting and essentially not readily breakable like shaving foams. At the other end of the spectrum the foam can be quick breaking and collapses upon release.

Thermolabile foams are an example of type of quick breaking foam. They can contain significant amounts of thermolabile substances that aid their collapse upon being exposed to an increased temperature for example when applied to a body surface at 37 C. Upon being exposed to the higher temperature they collapse rapidly. Examples are foam formulations that comprise significant amounts of volatile solvents.

Breakable foam is a specialized type of foam. It is a low density foam that is stable on release at least in the short time span of several minutes, which facilitates application to a target area; but can break readily upon the application of shear force such as gentle rubbing to spread easily over a target surface. It is not thermolabile (and does not melt at skin temperature) and nor does it display late or long delayed expansion over minutes. In some embodiments, the compositions described herein produce breakable foams.

Some foams expand slowly whilst others do so quickly. Some foams foam immediately and some demonstrate delayed foaming. Some require mechanical lathering and some expulsion by propellant. Whilst they all fall under the so called term “foam” and may appear to have some common ingredients the results and properties of these products are different.

A suitable foamable formulation for a particular application may present challenges at several levels. For example, a foam formulation may require a stable pre foam formulation; a stable pre foam propellant formulation (e.g., a foamable carrier) and ultimately delivery an effective measured amount of active agent to a target. Each of these objectives poses its own unique challenges.

The pharmaceutical and cosmetic foams discussed herein are generated in general terms by manufacturing a suitable foamable carrier composition and loading the carrier in a pressurized valved canister with an appropriate propellant. Upon expelling the canister contents a foam can be released. The type, nature and quality of the foam depends inter alia on the carrier composition, the active agent, the propellant and the method of manufacture and storage. Making a stable (physically and chemically) formulation that can be stored in a canister with a propellant that remains stable and can produce a breakable foam of quality on release is far from trivial.

An additional difficulty frequently encountered with propellant foams is their inability to dispense a uniform application of the medically active ingredient throughout the use of the entire aerosol container. This is particularly due to the fact that the active material is not stably dispersed in the foamable composition so that it will have a tendency to settle to the bottom. Further, the dispersed material will sometimes clog the spray dispensing valve to further interfere with the uniform dispensing of the medicament.

SUMMARY

There remains an unmet need for improved, easy to use, stable and non-irritating oil based foam formulations, with unique physical, therapeutic or beneficial properties containing a stable or stabilized active pharmaceutical or cosmetic agent. Moreover, there is an unmet need for waterless and substantially oil based waterless carriers and foam formulations with liquid silicone, which have a good or special skin feeling and which provide many of the desirable attributes of water based emulsions and foams, such as pleasant feeling, absence of stickiness, good spreadability, relatively quick absorption, absence of shine and reduced oily sensation

Compositions formulated using a base comprising an oil combined with liquid silicones to produce waterless formulations are investigated and developed herein as pharmaceutical and cosmetic waterless carriers suitable for delivery of a wide range of active agents despite the defoaming properties of silicones. In particular, such carriers that are substantially a single phase and, in some embodiments, are substantially free of particles. Moreover such carriers are ideal for oil soluble active agents and can nevertheless carry as a homogenous suspension substantial amounts of oil insoluble active agents.

In one aspect, a waterless foamable pharmaceutical composition including a foamable carrier and at least one liquefied or compressed gas propellant is disclosed. The foamable carrier includes: (i) about 60% to about 95% by weight of at least one liquid oil; (ii) a silicone; and (iii) at least one foam stabilizing agent. The foamable carrier is substantially a single phase. The foam stabilizing agent is selected from the group consisting of about 0.01% to about 25% by weight of at least one surface-active agent alone or in combination with a foam adjuvant; about 0% to about 5% by weight of at least one polymeric agent alone or in combination with a foam adjuvant and mixtures thereof. The ratio of the foamable carrier to the propellant is 100:03 to 100:35.

In some embodiments, the waterless foamable pharmaceutical composition includes, by weight: (i) about 60-90% mineral oil; (ii) about 1-15% of one or more of cyclomethicone; a mixutre of cyclohexasiloxane and cyclopentasiloxane, cyclytetrasiloxane, dimethiconol, phenyl trimethicone, stearyl dimethicone or mixtures thereof; (iii) about 1-8% glycerol monostearate; and (iv) about 1-8% myristyl alcohol or cetostearyl alcohol; and the composition is essentially free of water.

In another aspect, a waterless foamable pharmaceutical composition is provided. The composition includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes:

a) about 60% to about 95% by weight of at least one liquid oil;

b) a silicone; and

c) about 0.01% to about 25% by weight of a monoglyceride, diglyceride, or triglyceride, or a mixture thereof, wherein the side chain of the monoglyceride, diglyceride, or triglyceride is a saturated hydrocarbon.

The foamable carrier is substantially a single phase; and the ratio of the foamable carrier to the propellant is 100:03 to 100:35.

According to some embodiments, the fatty acid side chain of the monoglyceride, diglyceride, or triglyceride, or a mixture thereof, contains at least 8 carbon atoms. According to some embodiments, the monoglyceride, diglyceride, or triglyceride, or a mixture thereof, is a stearic-acid derived ester. According to some embodiments, the monoglyceride, diglyceride, or triglyceride, or a mixture thereof is glycerol monostearate or glycerol palmitostearate.

In some embodiments, the silicone used in the compositions described herein is a cyclic silicone, a branched silicone, a polar silicone or a mixture thereof. Exemplary cyclic silicones include, without limitation siloxane compounds having 4-6 Si—O groups in its backbone. In some embodiments, the cyclic silicone is a cyclomethicone. Exemplary branched silicones include, without limitation, phenyl trimethicone, steraryl methicone, cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18 dimethicone, and mixtures thereof. Exemplary polar silicones include, without limitation dimethiconol or PEG/PPG 18/18 dimethicone

In some embodiments, the at least one liquid oil used in the compositions described herein comprises mineral oil. Nonlimiting examples of oils for use in the foamable carriers described herein include mineral oil, MCT oil, liquid paraffin, vegetable oil, essential oil, organic oil, lipid, or a mixture thereof. In some embodiments, the oil is a mixture of light mineral oil and heavy mineral oil. In some embodiments, the weight ratio of the heavy mineral oil to the light mineral oil ranges from about 1:5 to about 25:1.

In some embodiments, the foamable carriers described herein further comprise an emollient. Examples of emollients for use in the compositions described herein include, without limitation, cocglycerides, PPG 15 stearyl alcohol, octyldodecanol, isopropyl myristate, diisopropyl adipate, cetearyl octanoate isohexadecanol, diisopropyl adipate and mixtures thereof.

In some embodiments, the foamable carriers described herein further comprise a solid wax or solid oil. Exemplary solid wax or oil include, without limitation solid paraffin, hydrogenated oil, hydrogenated emollient, palmitic acid, stearic acid, arachidic acid, behenic acid and mixtures thereof.

In some embodiments, the foam adjuvant used in the compositions described herein is a solid. Nonlimiting examples of solid foam adjuvants include a solid fatty alcohol selected from the group consisting of stearyl alcohol, cetyl alcohol, cetostearyl alcohol, myristyl alcohol, palmitoleyl alcohol, arachidyl alcohol, benhyl alcohol and mixtures thereof. In some embodiments, the foam adjuvant comprises oleyl alcohol.

In some embodiments, the surface active agent used in the compositions described herein is a stearic acid derived ester. In other embodiments, the surface active agent is monoglyceride, diglyceride, or triglyceride, wherein the side chain of the monoglyceride, diglyceride, or triglyceride is a C8-C24saturated hydrocarbon. Exemplary surface active agents include, without limitation, glycerol monostearate, glycerol palmitostearate, PEG 100 Stearate, Montanov L, Montano 68, PPG 15 stearyl ether or a mixture thereof.

In some embodiments, the surface active agent used in the compositions described herein is a solid.

In some embodiments, the weight ratio of surface active agent to silicone in the compositions described herein ranges from about 1:1 to about 1:4.

In some of the compositions described herein, (i) the liquid oil consists essentially of mineral oil; (ii) the silicone is present in the foamable carrier in an amount of about 0.5% to about 15% by weight; and (iii) the at least one stabilizing agent is glycerol monostearate and is present in the foamable carrier in an amount of about 0.01% to 25% by weight.

In some embodiments the waterless foamable pharmaceutical compositions described above also include an active agent. In some embodiments, the active agent is soluble in the liquid oil, the silicone, the surfactant or the composition. In some embodiments, the foamable carrier including the active agent forms a substantially homogenous suspension.

Exemplary active agents include active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotic agents, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, anti-yeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, immunosuppressants, immunoregulating agents, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapy agents, retinoids, sanatives, scabicides, self tanning agents, skin whitening agents, asoconstrictors, vasodilators, vitamins A, B, C, D, E and K and their derivatives, wound healing agents, wart removers and mixtures thereof.

In some embodiments, the active agent is a tetracycline antibiotic agent. Exemplary tetracycline antibiotic agents include, without limitation minocycline or doxycycline.

Nonlimiting examples of active agents include acyclovir, azaleic acid, clindamycin phosphate, pimicrolimus, diclofenac potassium; calcipotriol, calcitriol, vitamin A acetate, betamethasone 17-valerate, alpha tocopherol, Imiquimod, ciclopiroxolamine, and mixtures thereof.

A method of delivering an active agent to a patient in need of treatment, the method including administering a foamable pharmaceutical composition described herein to a skin surface, a mucosal surface, or a body cavity is also disclosed.

A method for treating skin or a mucosal surface including administering to the skin or mucosal surface a pharmaceutically effective amount of a foamable pharmaceutical composition described herein is disclosed.

A method for treating, ameliorating or preventing a disorder including administering to a target site a pharmaceutically effective amount of a foamable pharmaceutical composition described herein is disclosed. In some embodiments, the methods for treatment described herein include a combination of at least two active agents. In some embodiments, the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum.

In some embodiments, the waterless foamable pharmaceutical compositions described herein produce a resultant foam that displays all of the following characteristics

a. at least of good quality;

b. does not collapse immediately upon release;

c. is breakable on mechanical shear;

d. has a density below about 0.2 g/ml; and

e. has a collapse time in excess of about 180 seconds.

In some embodiments, the waterless foamable pharmaceutical compositions described herein produce a resultant foam that displays all of the following characteristics:

a. at least of good quality;

b. does not collapse immediately upon release;

c. is breakable on mechanical shear;

d. has a viscosity below about 13,000 cps;

e. has an average bubble size below 200 microns;

f. has a hardness between about 5 to about 35 and

e. has a collapse time in excess of about 180 seconds.

In another aspect, a method for preparing a substantially single phase, waterless foamable pharmaceutical composition is provided. The method includes the steps of:(a) combining about 60% to about 95% by weight of at least one liquid oil with at least one foam stabilizing agent at a temperature of at least about 50° C.;(b) rapidly cooling the combination of one liquid oil and at least one foam stabilizing agent to less than 40° C.;(c) adding a silicone to the cooled combination to make a prefoam formulation; and(d) combining the prefoam formulation with a compressed gas propellant in a weight ratio of 100:3 to 100:35.
In the method described above, the foam stabilizing agent is selected from the group consisting of about 0.01% to about 25% by weight of at least one surface-active agent alone or in combination with a foam adjuvant; about 0% to about 5% by weight of at least one polymeric agent alone or in combination with a foam adjuvant and mixtures thereof. The method for preparing a substantially single phase, waterless foamable pharmaceutical composition is useful for preparing the pharmaceutical compositions and foamable carriers described herein.

In another aspect, a method for preparing a substantially single phase, waterless foamable pharmaceutical composition is provided. The method includes the steps of:(a) preparing a prefoam formulation by combining at a temperature of at least about 50° C.:about 60% to about 95% by weight of at least one liquid oil; a silicone; and at least one foam stabilizing agent;(b) rapidly cooling the prefoam formulation to less than 40° C.; and(c) combining the prefoam formulation with a compressed gas propellant in a weight ratio of 100:3 to 100:35.
The foam stabilizing agent is selected from the group consisting of about 0.01% to about 25% by weight of at least one surface-active agent alone or in combination with a foam adjuvant; about 0% to about 5% by weight of at least one polymeric agent alone or in combination with a foam adjuvant and mixtures thereof.

In some embodiments of the preparation methods described herein, the cooling step is carried out by placing the combination of one liquid oil and at least one foam stabilizing agent in an ice bath, in an alcohol water bath or in a water bath or jacket.

In some embodiments of the preparation methods described herein, the combination of one liquid oil and at least one foam stabilizing agent is cooled at a rate of at least about 5 degrees/minute.

In some embodiments of the preparation methods described herein, the combination of one liquid oil and at least one foam stabilizing agent is cooled to a temperature of at least about 25° C.

