US 20100310476A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0310476A1 Tamarkin et al. (43) Pub. Date: Dec. 9, 2010

(54) CARRIERS, FORMULATIONS, METHODS (22) Filed: Jun. 7, 2010 FOR FORMULATING UNSTABLE ACTIVE AGENTS FOR EXTERNAL APPLICATION (30) Foreign Application Priority Data AND USES THEREOF Dec. 8, 2008 (IB) ...... PCTAIB2008/OO3932 (75) Inventors: Dov Tamarkin, Maccabim (IL); Doron Friedman, Karmei Yosef Publication Classification (IL); Meir Eini, Ness Ziona (IL); (51) Int. Cl. Alex Besonov, Rehovot (IL); A6IR 9/12 (2006.01) Helena Shifrin, Rehovot (IL) A6IP3L/00 (2006.01) A6IP3L/04 (2006.01) Correspondence Address: A6IP4/00 (2006.01) WILMERHALEABOSTON 6O STATE STREET (52) U.S. Cl...... 424/43 BOSTON, MA 02109 (US) (57) ABSTRACT (73) Assignee: Foamix Ltd., Ness Ziona (IL) The present disclosure teaches unique formulations for topi cal administration of tetracycline antibiotics, in which the (21) Appl. No.: 12/795,164 tetracycline antibiotics remain stable. Patent Application Publication Dec. 9, 2010 US 2010/0310476A1

F.G. 1 Corneometer Values (Mean +SE)

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ease NO bo Cetaphil-e-PMCH-017P -e-PanOxy. Treat US 2010/031 0476 A1 Dec. 9, 2010

CARRIERS, FORMULATIONS, METHODS skin. An additional disadvantage of petroleum jelly-based FOR FORMULATING UNSTABLE ACTIVE products relates to the greasy feeling left following their AGENTS FOR EXTERNAL APPLICATION topical application onto the skin, mucosal membranes and AND USES THEREOF wounds. A further problem of non aqueous compositions is achieving formulations in which the active agent is stable. CROSS REFERENCE TO RELATED 0005. Some active agents are known to be generally APPLICATIONS unstable or Susceptible to isomerisation or to breakdown, 0001. This application claims the benefit under 35 U.S.C. resulting in loss of activity and the use of Stabilizers, anti S371 to PCT/IB2008/03932, filed on Dec. 8, 2008, which oxidants antimicrobials and buffers and the like in aqueous claims priority under 35 U.S.C. S 119(e) of U.S. Provisional compositions to protect active or cosmetic agents is known. Patent Application No. 61/012,414, filed on Dec. 7, 2007, The problems of protecting active pharmaceutical and cos entitled “Carriers. Formulations, Methods for Formulating metic agents in waterless environments, such as polar com Unstable Active Agents for External Application and Uses positions are multifold and can vary according to the type of Thereof, and U.S. Provisional Patent Application No. waterless environment and the nature of the agent being used. 61/103,500, filed on Oct. 7, 2008 entitled “Oil and Liquid It has been surprisingly found that factors like small levels of Silicone Carriers and Formulations for External and Body acid residues in the raw materials can be significant in influ Cavity Application of Active Agents and Uses Thereof.” each encing agent stability. Similarly, the presence of low levels of of which is herein incorporated by reference in its entirety. metal ions can act to catalyze reactions or breakdown. Like wise, the presence of agents in a waterless environment that FIELD results in ionization or leads to oxidation can act to cause reactions or breakdown. There is therefore a need for simple 0002. This disclosure relates to materials, carriers, formu and elegant solutions to stabilize active ingredients in a water lations and methods for formulating unstable active agents in less or Substantially environment. topical compositions, which are Suitable, interalia, for apply 0006. It would be particularly advantageous and there is an ing to the skin or to mucosal Surfaces and can be used for unmet need to have a waterless vehicle additive that is suitable treating topical, mucosal and or systemic disorders in mam for use not merely one type of active pharmaceutical ingre mals. The disclosure further relates to vehicles which are dient (API) but is adaptable for use with one or more API's suitable, inter alia, for delivery for a wide range of active from a wide range of different types of API's with relatively pharmaceutical and cosmetic agents and methods for their minimal or minor adjustment. SC. 0007 Foams and, in particular, foam emulsions are com plicated systems which do not form under all circumstances. BACKGROUND Changes in foam emulsion composition, such as by the addi 0003. The skin is the largest organ of a mammalian body, tion of active ingredients may destabilize the foam. There is, serving many important functions, such as regulating body therefore, a need for a foam composition, which provides temperature, maintaining water and electrolyte balance, and desirable properties to the skin and can remain stable whilst sensing painful and pleasant stimuli. The skin is adapted to accommodating a variety of active ingredients. keep dangerous Substances from entering the body and pro 0008 Formulations based on oil or ointment or emollients vides a shield from the harmful effects of the Sun. Any dete have a number of useful attributes making them suitable rioration in skin health may have important consequences on candidates for topical pharmaceutical and cosmetic compo a person's physical and mental health. Many teenagers Suffer sitions including foamable compositions. They are inherently from acne, which is an inflammatory disease of the skin, stable and inert which are clearly desirable characteristics. caused by changes in the pilosebaceous units and results in They are able to moisturize and soften the skin and in appro scarring or hyperpigmentation of the skin. Several types of priate amounts can act as a protective or barrier layer and can skin disorder manifest themselves as rashes and lead to itch form a barrier to water. By appropriate formulation they can ing. The itching and rashes may develop as the result of act to improve drug delivery to the skin and yet remain resis infection or irritation or from an immune system reaction. tant to being washed off. On the other hand they are by their Additionally, the skin is prone to microbial infection and nature greasy materials and can be difficult to formulate par parasitic infestation. ticularly into a topical foamable composition that can deliver 0004 External topical administration is an important Substantially uniform and stable composition or foam that route for the administration of drugs in both systemic and ameliorates or overcomes the look and feel of a greasy mate topical disease treatment. Many groups of drugs, including, rial, especially where that composition is waterless or Sub for example, antibiotic, anti-fungal, anti-inflammatory, anes stantially so. It is further a problem to incorporate into Such a thetic, analgesic, anti-allergic, corticosteroid, retinoid and vehicle pharmaceutically effective amounts of one or more anti-proliferative medications are preferably administered in active pharmaceutical ingredients such that they are uni hydrophobic media, namely ointment. However, ointments formly present throughout the formulation and are effectively often form an impermeable barrier, thus in the treatment of a delivered without the use of an alcohol in the formulation. topical wound, metabolic products and excreta from these 0009. On one level it is far from simple or obvious to wounds to which they are applied are not easily removed or produce waterless foamable compositions that when released drained away. Furthermore, it is difficult for the active drug produce foams of quality Suitable for pharmaceutical or cos dissolved in the carrier to pass through the white petrolatum metic application. On a further level having realized a carrier barrier layer into the wound tissue, so the efficacy of the drug that will produce a waterless foam of quality there is an is reduced. In addition, ointments and creams often do not additional difficulty to be overcome, namely how to adapt the create an environment for promoting respiration of the wound formula and achieve a formulation, which can accept a range tissue and it is not favorable to the normal respiration of the of various active pharmaceutical and cosmetic agents such US 2010/031 0476 A1 Dec. 9, 2010 that the composition and active agent are stable and the foam higher temperature they collapse rapidly. Examples are foam produced remains of quality. Specifically, one of the chal formulations that comprise significant amounts of Volatile lenges in preparing Such waterless or Substantially waterless Solvents. foamable compositions is ensuring that the active pharma 0016 Breakable foam is a specialized type of foam. It is a ceutical or therapeutic agent does not react, isomerizes or low density foam that is stable on release at least in the short otherwise break down to any significant extent during is stor time span of several minutes, which facilitates application to age and use. Particularly, there remains an unmet need for a target area; but can break readily upon the application of improved, easy to use, stable and non-irritating foam formu shear force Such as gentle rubbing to spread easily over a lations, with unique therapeutic or beneficial properties con target Surface. It is not thermolabile (and does not melt at skin taining a stable or stabilized active pharmaceutical or cos temperature) and nor does it display late or long delayed metic agent. expansion over minutes. 0010. There remains an unmet need for improved, easy to 0017. Some foams expand slowly whilst others do so use, stable and non-irritating topical foam formulations con quickly. Some foams foam immediately and some demon taining a stable or stabilized active pharmaceutical or cos strate delayed foaming. Some require mechanical lathering metic agent having atherapeutic or beneficial effect, intended and some expulsion by propellant. Whilst they all fall under for treatment of dermal and mucosal tissues. the so called term “foam and may appear to have some 0011 Systemic administration of active agents often leads common ingredients the results and properties of these prod to allergic responses, side effects and bacterial resistance to ucts are different. the active agents. There thus remains an unmet need for 0018. A suitable foamable formulation for a particular improved, easy to use, stable and non-irritating anti-infective application may present challenges at several levels. For foam formulations comprising active agents, intended for example, a foam formulation may require a stable pre foam treatment, interalia, of dermal and mucosal tissues. Particu formulation; a stable pre foam propellant formulation and larly, there remains an unmet need for improved, easy to use, ultimately delivery an effective measured amount of active stable and non-irritating anti-infective foam formulations, agent to a target. Each of these objectives poses its own with unique therapeutic properties. unique challenges. 0012 Foams are complex dispersion systems which do 0019. The pharmaceutical and cosmetic foams discussed not form under all circumstances. Slight shifts in foam com herein are generated in general terms by manufacturing a position, Such as by the addition of active ingredients, may Suitable foamable carrier composition and loading the carrier destabilize the foam. Foams are very complex and sensitive in a pressurized valved canister with an appropriate propel systems and are not formed at will. Mere addition of basic lant. Upon expelling the canister contents a foam can be ingredients like oil, Surfactant and propellant is far from Suf released. The type, nature and quality of the foam depends ficient to produce foams of quality that are homogenous, inter alia on the carrier composition, the active agent, the stable, breakable upon mechanical force and can be used to propellant and the method of manufacture and storage. Mak provide a shelf stable pharmaceutical or cosmetic composi ing a stable (physically and chemically) formulation that can tion. Small deviations may lead to foam collapse. Much con be stored in a canister with a propellant that remains stable sideration needs to be given to facilitate the introduction of an and can produce a breakable foam of quality on release is far active agent, such as examining compatibility and non reac from trivial. tivity with the various excipients and container and determin 0020. An additional difficulty frequently encountered ing shelf life chemical stability. with propellant foams is their inability to dispense a uniform 0013 Neubourg (US 2006/0099151), for example, notes application of the medically active ingredient throughout the that the stability of foam is strongly dependent on the specific use of the entire aerosol container. This is particularly due to composition of the foam forming components, so that even the fact that the active material is not stably dispersed in the Small deviations in the composition may lead to a collapse of foamable composition so that it will have a tendency to settle the foam. Gordon et al. (U.S. Pat. No. 3.456,052). also to the bottom. Further, the dispersed material will sometimes teaches that one cannot generate a good quality foam by clog the spray dispensing valve to further interfere with the simply adding a propellant to a mixture of components: uniform dispensing of the medicament. 0014. The term “foam is a general term that encompasses a range of Substances. Accordingly, the context in which SUMMARY “foam is discussed must be examined carefully. The type and 0021. In one aspect, the present disclosure relates to a quality of the foam is of critical importance. There are many topical antibiotic composition comprising a foamable phar different types of foams and within each foam type there are maceutical composition and a propellant, the foamable phar many levels of qualities. For example, the froth on the head of maceutical composition comprising: a) about 0.1% to about beer, lather of shampoo, and lather of shaving cream have 10% by weight of a tetracycline antibiotic; b) about 60% to been loosely described as foam but all are different from one about 95% by weight of: at least one oily emollient; at least another. At one end of the cosmetic or pharmaceutical foam one oil, wherein the oil is a liquid hydrocarbon-based oil; or spectrum the foam can be long lasting and essentially not a combination of at least one oily emollient and at least one readily breakable like shaving foams. At the other end of the oil; c) about 0.01% to about 15% by weight of at least one spectrum the foam can be quick breaking and collapses upon Surfactant, wherein the Surface active agent is an ester of a release. C8-C24 saturated hydrocarbon; d) optionally 0.01% to about 0015 Thermolabile foams are an example of type of quick 10% by weight of at least one foam adjuvant, wherein the breaking foam. They can contain significant amounts of ther foam adjuvant is a 14C to 18C fatty alcohol; and wherein the molabile Substances that aid their collapse upon being tetracycline antibiotic is chemically stable in the foamable exposed to an increased temperature for example when pharmaceutical composition when Stored for 72 hours at applied to a body surface at 37 C. Upon being exposed to the about at least 25° C. after mixing with the pharmaceutical US 2010/031 0476 A1 Dec. 9, 2010

composition; and wherein the weight ratio of the foamable about 1% to about 10% by weight of at least one foam adju pharmaceutical composition to the propellant is about 100:5 vant selected from the group consisting of oleyl alcohol, to about 100:35. Stearyl alcohol, myristyl alcohol and Stearic acid wherein the 0022. In another aspect, the present disclosure relates to a doxycycline monohydrate is chemically stable in the foam topical antibiotic composition comprising a foamable phar able pharmaceutical composition when stored for 72 hours at maceutical composition and a propellant, the foamable phar about at least 25°C. after mixing with the foamable pharma maceutical composition comprising: a) about 0.1% to about ceutical composition; and wherein the weight ratio of the 10% by weight of minocycline hydrochloride; b) about 60% foamable pharmaceutical composition to the propellant is to about 95% by weight of: at least one emollient selected about 100:5 to about 100:35. from the group consisting of PPG-15 stearyl ether, octyldode 0025. In some embodiments, the oily emollient is selected canol, diisopropyl adipate, and Cetearyl Octanoate; at least from the group consisting of Cetearyl Octanoate, Cyclom one oil selected from the group consisting of Light mineral ethicone, PPG-15 Stearyl Ether, Propylene glycol, Octyl oil, MCT oil, Hydrogenated Castor Oil, jojoba oil, and pep dodecanol, Glycerol, Diisopropyl adipate, and isostearic permint oil; or a combination of at least one emollient and at acid. In other embodiments, the oily emollient is selected least one oil; c) about 0.01% to about 15% by weight of at from the group consisting of PPG-15 stearyl ether, octyldode least one Surfactant selected from the group consisting of canol, diisopropyl adipate, isostearic acid, and cetearyl Glycerol monostearate, Sorbitan monostearate (Span 60), Octanoate. PEG 40 Stearate (MyriS2), and PEG 100 Stearate (MyriS9); 0026. As used herein, an oil is a liquid hydrocarbon-based d) optionally about 0% to about 10% by weight of at least one oil. Non-limiting examples of oils include plant-based oils, foam adjuvant selected from the group consisting of Oleyl mineral oils, triglycerides, essential oils, and animal-based alcohol, Stearyl alcohol, Myristyl alcohol and Cocoglycer oils. Without being limited to any particular theory, oils are ides; and wherein the minocycline hydrochloride is chemi believed to be effective in the claimed formulations because cally stable in the foamable pharmaceutical composition they limit the potential for oxidation of the tetracycline anti when stored for 72 hours at about at least 25°C. after mixing biotics. In some embodiments of the present disclosure, the with the carrier or with the agent; and wherein the weight ratio oil is selected from the group consisting of plant-based oil, of the foamable pharmaceutical composition to the propellant mineral oil, triglyceride, essential oil, and animal-based oil. is about 100:5 to about 100:35. In other embodiments, the oil is selected from the group 0023. In another aspect, the present disclosure relates to a consisting of light mineral oil, MCT oil, hydrogenated castor topical antibiotic composition comprising a foamable phar oil, jojoba oil, and peppermint oil. maceutical composition and a propellant, the foamable phar 0027. In some embodiments, the surfactant is a stearic acid maceutical composition comprising: a) about 0.1% to about derived ester. In other embodiments the surfactant is 10% by weight of doxycycline hyclate; b) about 60% to about monoglyceride, diglyceride, or triglyceride, wherein the side 95% by weight of: at least one emollient selected from the chain of the monoglyceride, diglyceride, or triglyceride is a group consisting of PPG-15 stearyl ether, diisopropyladipate, C8-C24 saturated hydrocarbon. In still other embodiments and Cetearyl Octanoate; at least one oil selected from the the Surfactant is selected from the group consisting of Glyc group consisting of mineral oil and MCT oil; or a combina erol monostearate, glycerol palmitostearate, Sorbitan tion of at least one emollient and at least one oil; c) about monostearate (Span 60), PEG 40 Stearate (MyriS2), and PEG 0.01% to about 15% by weight of at least one surfactant 100 Stearate (Myri 59). selected from the group consisting of Glycerol monostearate, 0028. In some embodiments of the present disclosure, the Sorbitan monostearate (Span 60), hydrogenated castor oil, foam adjuvant selected from the group consisting of oleyl and PEG 100 Stearate (Myri 59); d) optionally about 0% to alcohol, Stearyl alcohol, myristyl alcohol and cocoglycerides. about 10% by weight of at least one foam adjuvant selected 0029. In some embodiments of the present disclosure, the from the group consisting of steryl alcohol, oleyl alcohol, tetracycline antibiotic is selected from the group consisting of isostearic acid and myrystyl alcohol, wherein the doxycycline minocycline hydrochloride, doxycycline hyclate, and doxy hyclate is chemically stable in the foamable pharmaceutical cycline monohydrate. composition when stored for 72 hours at about at least 25°C. 0030. In some embodiments, the topical antibiotic com after mixing with the foamable pharmaceutical composition; position further comprises at least one of ethanol 95%, alu and wherein the weight ratio of the foamable pharmaceutical minum starch octenylsuccinate, titanium dioxide, coconut composition to the propellant is about 100:5 to about 100:35. alcohol, and hexylene glycol. 0024. In another aspect, the present disclosure relates to a 0031. In some embodiments of the present disclosure, topical antibiotic composition comprising a foamable phar chemical stability is determined by observing a color change maceutical composition and a propellant, the foamable phar in the foamable pharmaceutical composition. In some maceutical composition comprising: a) about 0.1% to about embodiments, chemical stability is determined by measuring 10% by weight of doxycycline monohydrate; b) about 60% to at least about 90% by mass of the tetracycline antibiotic at 72 about 95% by weight of: at least one emollient selected from hours compared to time 0. In some embodiments, chemical the group consisting of Cetearyl Octanoate, Cyclomethicone, stability is determined by measuring less than about 1% by PPG-15 Stearyl Ether, Propylene glycol, Octyldodecanol, mass of 4-epiminocylcine at 72 hours compared to time 0. Glycerol, Diisopropyl adipate, and isostearic acid; at least 0032. In some embodiments of the present disclosure, the one oil selected from the group consisting of Light mineral topical antibiotic composition further comprises at about oil, MCT Oil, and hydrogenated castor oil; or a combination 0.1% to about 5% of a silicone oil. In some embodiments the of at least one emollient and at least one oil; c) about 0.01% to silicone oil is cyclomethicone. about 15% by weight of at least one surfactant selected from 0033. In some embodiments of the present disclosure, the the group consisting of Glycerol monostearate, Sorbitan topical antibiotic composition further comprises at least one monostearate (Span 60), and PEG 100 Stearate (Myri 59); d) additional active agent. US 2010/031 0476 A1 Dec. 9, 2010

0034. Also disclosed herein are methods of treating a bac in an associated or unfree or absorbed form and may absorb terial infection comprising topically administering the topical water from the atmosphere and the ability to do so is its antibiotic composition to a Subject in need of treatment. In hygroscopic water capacity. Some embodiments, the topical antibiotic composition is 0045. In one or more embodiments the carrier comprises administered to the skin, a mucosal membrane, or a body an active pharmaceutical or cosmetic agent, which degrades cavity. In other embodiments, the topical antibiotic compo in the presence of water, and in Such cases the present of water sition is administered to a wound, an ulcer, or a burn. in the composition is clearly not desirable. Thus, in certain 0035 Also disclosed herein are methods of treating and preferred embodiments, the composition is waterless. In preventing post-Surgical adhesions, the method comprising other embodiments the active agent may tolerate the presence topically administering the topical antibiotic composition to a of a small amount of water and the waterless composition is Surgical site of a subject. Substantially non-aqueous. The term "substantially non 0036. In some embodiments of the methods disclosed aqueous” is intended to indicate that the waterless composi herein, the topical antibiotic composition further comprises at tion has water content preferably below about 2%, such as least one additional active agent. below about 1.5%. 0037. In some embodiments of the present disclosure, the 0046. In some cases the foamable carrier further includes tetracycline antibiotic is chemically stable in the foamable a liquefied or compressed gas propellant at a concentration of pharmaceutical composition when stored for 72 hours at about 3% to about 25% by weight. about at least 40°C., or at least about 50° C., after mixing with 0047. The waterless foamable pharmaceutical composi the pharmaceutical composition. In still other embodiments, tion maybe substantially chemically stable, defined as dem the tetracycline antibiotic is chemically stable in the foamable onstrating Substantially no or minimal color change due to pharmaceutical composition when stored for about 3 weeks at oxidation 72 hours after mixing with the carrier or agent when about at least 25°C., about at least 40°C., or about at least 50° stored at about at least 25°C. C. 0048. Additionally, “chemically stable' or “chemical sta bility” may be defined as demonstrating substantially no or BRIEF DESCRIPTION OF THE DRAWINGS minimal breakdown from oxidation 72 hours after mixing with the carrier or agent when stored at about at least 25°C. 0038 FIG. 1 is a graph presenting corneometer values Substantially no or minimal breakdown may be determined generated using Cetaphil, PanOxyl, PMCH-017P and no using HPLC methods disclosed herein or other methods, treatment on the skin of healthy volunteers. where the mass of the compound is determined at time 0 (i.e., within about 1 hour after mixing with the carrier or foamable DETAILED DESCRIPTION pharmaceutical composition) and about 72 hours after mix 0039. Many classes of materials may be used in topical ing, and wherein at least about 90% by mass of the compound pharmaceutical formulations, including emollients, oils, sili is detected at about 72 hours compared to time 0. Alterna cone oils, polymeric agents, Surface-active agents (i.e., Sur tively, degradation products may be determined using HPLC factants), Solid matter agents, foam adjuvants, solvents, skin methods disclosed herein or other methods, where the mass of penetration enhancers, potent solvents, modulating agents, the degradation products is determined at time 0 and about 72 anti-oxidants, and radical scavengers. However, tetracycline hours after mixing, and wherein less than about 1% by mass antibiotics are susceptible to oxidation, and are thus generally of the compound in the mixture is degradation products. chemically unstable in topical formulations. Therefore, When the compound is minocycline, a Suitable degradation chemically stable topical formulations of tetracycline antibi product for purposes of determining “chemical stability” or otics are generally challenging to prepare. To achieve foam “chemically stable' is 4-epiminocycline. able formulations using propellant that are both physically 0049. The minocycline may be provided in a substantially and chemically stable is a highly complex and unpredictable homogenous insoluble Suspension. challenge. 0050. The waterless foamable pharmaceutical composi 0040 Some embodiments of the present disclosure are tion may further include about 1 to about 2% minocycline directed to a waterless foamable pharmaceutical composition hydrochloride. Suitable for external administration of minoycline, including: 0051. The at least one oily carrier may be selected from an 0041 at least one least one minocycline-compatible emollient, an oil and a foam adjuvant. (MC) oily carrier; and 0.052 The emollient may be selected from cyclomethi 0042 at least one least one minocycline-compatible cone; isopropyl myristate, PPG-15 stearyl ether; octyldode (MC) stabilizing agent; canol; Isohexadecanol, diisopropyl adipate; and Cetearyl 0043 wherein the stabilizing agent selected from the Octanoate. group consisting of about 0.01% to about 25% by weight of at 0053 According to some embodiments, the oil is selected least one surface-active agent alone or in combination with a from hydrogenated castor oil and MCT oil. foam adjuvant; about 0% to about 5% by weight of at least one 0054 Additionally, the foam adjuvant is selected from polymeric agent and mixtures thereof, wherein MC is defined Oleyl alcohol, Stearyl alcohol, Myristyl alcohol and by minocycline remaining Substantially chemically stable, 72 Cocoglycerides. hours after mixing with the carrier or with the agent. 0055. The surfactant may be selected from Glycerol 0044. By waterless is meant that the composition contains monostearate, Polysorbate 80, Polysorbate 60, Sucrose dis no or Substantially no, free or unassociated or absorbed water. tearate, Polyoxyl 20 Stearyl Ether, Polyoxyl 2 Stearyl Ether, It will be understood by a person of the art that to the extent Sorbitan monostearate, Ester HLB 11, GMS-PEG 100 Stear the waterless solvents and substances miscible with them of ate, Polysorbate 80, Polysorbate 60, Sorbitan monostearate the present disclosure are hydrophilic they can contain water (Span 60), Methy Glucose Sesquistearate, PEG 40 Stearate US 2010/031 0476 A1 Dec. 9, 2010

(Myri 52), PEG 100 Stearate (Myri 59), Montanov S. Glyc bate 60, Sorbitan monostearate (Span 60), Methy Glucose eryl monostearate, and Sepigel 305. Sesquistearate, PEG 40 Stearate (MyriS2), PEG 100 Stearate 0056. Some embodiments include a waterless foamable (Myri 59), Montanov S. Glyceryl monostearate, and Sepigel pharmaceutical composition including: 305. 0057 6% to 80% by weight of at least one oily carrier 0072 Some embodiments of the present disclosure are Selected from the group consisting of Cyclomethicone, directed to a waterless foamable pharmaceutical composition PPG-15 Stearyl Ether, Octyldodecanol, Isohexade including: canol, Diisopropyl adipate, Cetearyl Octanoate, Light 0.073 6% to 80% by weight of at least one oily carrier mineral oil, and Hydrogenated Castor Oil; and Selected from the group consisting of Cyclomethicone, 0058 0.01% to 25% by weight of at least one stabilizing PPG-15 Stearyl Ether, Octyldodecanol, Isohexade agent selected from the group consisting of Glycerol canol, Diisopropyl adipate, Cetearyl Octanoate, Light monostearate, Polysorbate 60, Polysorbate 80. Sucrose mineral oil, and Hydrogenated Castor Oil; and distearate, Polyoxyl 20, Stearyl Ether, Polyoxyl 2 0074 0.01% to 25% by weight of at least one stabilizing Stearyl Ether, Sorbitan monostearate (Span 60), Methy agent is selected from the group consisting of Glycerol Glucose Sesquistearate, Myri 52, Myri 59, Montanov S. monostearate, Polysorbate 60, Polysorbate 80. Sucrose Glyceryl monostearate and Sepigel 305. distearate, Polyoxyl 20, Stearyl Ether, Polyoxyl 2 0059 A waterless foamable pharmaceutical composition Stearyl Ether, Sorbitan monostearate (Span 60), Methy may include: Glucose Sesquistearate, Myri 52, Myri 59, Montanov S. 0060 10% to 80% by weight of at least one oily carrier Glyceryl monostearate and Sepigel 305. Selected from the group consisting of Cyclomethicone, 0075 Other embodiments include a waterless foamable PPG-15 Stearyl Ether, Propylene Glycol, Octyldode pharmaceutical composition including: canol, Glycerol, Diisopropyl adipate, Cetearyl 0076) 10% to 80% by weight of at least one oily carrier Octanoate, Light Mineral oil, and MCT oil; and Selected from the group consisting of Cyclomethicone, 0061 0.01% to 6% by weight of at least one stabilizing PPG-15 Stearyl Ether, Propylene Glycol, Octyldode agent selected from the group consisting of Glycerol canol, Glycerol, Diisopropyl adipate, Cetearyl monostearate, Sucrose Ester HLB 11, GMS-PEG 100 Octanoate, Light Mineral oil, and MCT oil; and Stearate, Polysorbate 80, Polysorbate 60, Polysorbate 0.077 0.01% to 6% by weight of at least one stabilizing 20, Sorbitan monostearate, Methy Glucose Sesquistear agent selected from the group consisting of Glycerol ate, PEG 40 Stearate (MyriS2), PEG 100 Stearate (Myr monostearate, Sucrose Ester HLB 11, GMS-PEG 100 59), Hydrogenated Castor Oil, Steareth-2, Steareth-20, Stearate, Polysorbate 80, Polysorbate 60, Polysorbate Steareth-21 and Poloxamer 407 (20% gel). 0062 Some embodiments of the present disclosure are 20, Sorbitan monostearate, Methy Glucose Sesquistear directed to a waterless foamable pharmaceutical composition ate, PEG 40 Stearate (MyrS2), PEG 100 Stearate (Myri which is substantially chemically stable, defined as demon 59), Hydrogenated Castor Oil, Steareth-2, Steareth-20, strating Substantially no or minimal color change due to oxi Steareth-21 and Poloxamer 407 (20% gel). dation 72 hours after mixing with the carrier or agent. 0078 Yet further embodiments include a waterless foam 0063. According to some embodiments, the waterless able pharmaceutical suitable for external administration of foamable pharmaceutical composition is chemically stable, doxycycline, including: defined by showing substantially no or minimal breakdown 0079 at least one doxycycline-compatible (DC) oily one week after mixing with the carrier or agent. carrier, and 0064. According to some embodiments, the minocycline 0080 at least one doxycycline-compatible (DC) stabi is in a Substantially homogenous insoluble Suspension. lizing agent; 0065. The waterless foamable pharmaceutical composi I0081 wherein the stabilizing agent is selected from the tion may further include 3% to 25% by weight of a liquefied group consisting of about 0.01% to about 25% by weight of at or compressed gas propellant. least one surface-active agent alone or in combination with a 0066. According to some embodiments, the waterless foam adjuvant; about 0% to about 5% by weight of at least one foamable pharmaceutical composition may further include polymeric agent and mixtures thereof, and about 1 to about 2% minocycline hydrochloride. I0082 wherein DC is defined by doxycycline remaining 0067. Additionally, the at least one oily carrier is selected substantially chemically stable, 72 hours after mixing with from an emollient, an oil and a foam adjuvant. the agent. 0068 According to some embodiments, the emollient is 0083. Further embodiments relate to a waterless foamable selected from cyclomethicone, isopropyl myristate, PPG-15 pharmaceutical composition wherein Substantially chemi Stearyl ether, octyldodecanol, Isohexadecanol, diisopropyl cally stable is defined as demonstrating Substantially no or adipate, and Cetearyl Octanoate. minimal color change due to oxidation 72 hours after mixing 0069. According to some embodiments, the oil is selected with the carrier or agent. from hydrogenated castor oil and MCT oil. 0084. Further embodiments relate to a waterless foamable 0070 According to some embodiments, the foam adju pharmaceutical composition, wherein Substantially chemi vant is selected from Oleyl alcohol, Stearyl alcohol, Myristyl cally stability is defined as demonstrating Substantially no or alcohol and Cocoglycerides. minimal breakdown one week after mixing with the carrier or 0071. According to some embodiments, the surfactant is agent. selected from Glycerol monostearate, Polysorbate 80, I0085. The doxycycline is a substantially homogenous Polysorbate 60, Sucrose distearate, Polyoxyl 20 Stearyl insoluble Suspension. The waterless foamable pharmaceuti Ether, Polyoxyl 2 Stearyl Ether, Sorbitan monostearate, Ester cal composition may further include 3% to 25% by weight of HLB 11, GMS-PEG 100 Stearate, Polysorbate 80, Polysor a liquefied or compressed gas propellant. US 2010/031 0476 A1 Dec. 9, 2010

I0086. In some cases the waterless foamable pharmaceuti Cyclomethicone 5-NF (cyclopentasiloxane), stearyl dimethi cal composition further includes 0.5-2% doxycycline. For cone, phenyltrimethicone, cetyl dimethicone, caprylyl methi this purpose the at least one oily carrier may be selected from cone, PEG/PPG 18/18 dimethicone, or dimethiconol. an emollient, an oil and a foam adjuvant. the emollient may be 0099. According to some embodiments, the at least one selected from cyclomethicone; isopropyl myristate, PPG-15 Surface active agent is selected from the group consisting of at Stearyl ether, propylene glycol; octyldodecanol; glycerol; least one non-ionic Surfactant and at least one ionic Surfac diisopropyl adipate; and diisopropyl adipate; and the foam tant. adjuvant may be selected from Oleyl alcohol, Stearic acid, 0100. In some cases, the at least one surface active agent is Stearylalcohol, Myristyl alcohol and Cocoglycerides. The oil selected from the group consisting of polysorbate, polyoxy may be selected from light mineral oil and MCT oil. The at ethylene (20) sorbitan monostearate, polyoxyethylene (20) least one stabilizing agent is selected from a surfactant and a Sorbitan monooleate, a polyoxyethylene fatty acid ester, Myr polymeric agent. The Surfactant is selected from Glycerol 45, Myr 49, Myr 52 and Myri 59; a polyoxyethylene alkylyl monostearate, Sucrose Ester HLB 11; GMS-PEG 100 Stear ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ate: Polysorbate 80; Polysorbate 60; Polysorbate 20; Sorbitan ether, polyethylene oxide hexadecyl ether, polyethylene gly monostearate; Methy Glucose Sesquistearate; PEG 40 Stear col cetyl ether, brij 38, bri 52, brij 56 and brij W1, a sucrose ate (Myri 52); PEG 100 Stearate (Myri 59); Hydrogenated ester, a partial ester of Sorbitol, Sorbitan monolaurate, Sorbi Castor Oil: Steareth-2; Steareth-20: Steareth-21 and Polox tan monolaurate a monoglyceride, a diglyceride, isoceteth-20 amer 407 (20% gel). and a Sucrose ester. 0087 Preferred solvents for doxycycline and minocycline 0101 The foamable carrier may further including a foam include octyl dodecanol, oleyl alcohol and PPG 15 stearyl adjuvant selected from the group consisting of a fatty alcohol, ester. These compounds are monoalcohols and not polyols. a fatty acid and a hydroxyl fatty acid. 0088. Further embodiments include a waterless foamable 0102) According to some embodiments, wherein the foam pharmaceutical composition, including: adjuvant component may include at least one of the group I0089 6% to 80% by weight of the at least one oily consisting of Oleyl alcohol, Stearyl alcohol, Myristyl alcohol carrier; and and Cocoglycerides. (0090. 0.01% to 25% by weight of the at least stabilizing 0103) According to some further embodiments, the foam agent. able carrier may further include an additional component 0091. Further embodiments include a waterless foamable selected from the group consisting of an anti perspirant, an pharmaceutical composition: anti-static agent, a buffering agent, a bulking agent, a chelat 0092) 10 to 60% by weight of the at least one oily ing agent, a colorant, a conditioner, a deodorant, a diluent, a carrier; and dye, an emollient, fragrance, a humectant, an occlusive agent, (0093 0.01% to 10% by weight of the at least stabilizing a penetration enhancer, a perfuming agent, a permeation agent. enhancer, a pH-adjusting agent, a preservative, a skin pen 0094 Further embodiments include a waterless foamable etration enhancer, a Sunscreen, a Sunblocking agent, a Sunless pharmaceutical composition, including: tanning agent, and a vitamin. (0095) 10 to 60% by weight of the at least one oily 0104. According to some embodiments, the foamable car carrier; and rier may also include an additional active agent is selected (0096 0.01% to 6% by weight of the at least stabilizing from the group consisting of active herbal extracts, acari agent. cides, age spot and keratose removing agents, allergen, anal 0097. Some compositions comprise at least one hydropho gesics, local anesthetics, antiacne agents, antiallergic agents, bic solvent selected from the group consisting of mineral oil, antiaging agents, antibacterials, antibiotic agents, antiburn isopropyl palmitate, isopropyl isostearate, diisopropyl adi agents, anticancer agents, antidandruff agents, antidepres pate, diisopropyl dimerate, maleated soybean oil, octyl sants, antidermatitis agents, antiedemics, antihistamines, palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, antihelminths, antihyperkeratolyte agents, antiinflammatory acetylatedlanolin alcohol, cetyl acetate, phenyl trimethicone, agents, antiirritants, antilipemics, antimicrobials, antimy glyceryl oleate, tocopheryllinoleate, wheat germ glycerides, cotics, antiproliferative agents, antioxidants, anti-wrinkle arachidyl propionate, myristyl lactate, decyl oleate, ricino agents, antipruritics, antipsoriatic agents, antirosacea agents leate, isopropyl lanolate, pentaerythrityl tetrastearate, neo antiseborrheic agents, antiseptic, antiswelling agents, antivi pentylglycol dicaprylate/dicaprate, isononyl isononanoate, ral agents, anti-yeast agents, astringents, topical cardiovascu isotridecyl isononanoate, myristyl myristate, triisocetyl cit lar agents, chemotherapeutic agents, corticosteroids, dicar rate, octyl dodecanol, unsaturated or polyunsaturated oils, boxylic acids, disinfectants, fungicides, hair growth Such as olive oil, corn oil, soybean oil, canola oil, cottonseed regulators, hormones, hydroxy acids, immunosuppressants, oil, coconut oil, Sesame oil, Sunflower oil, borage seed oil, immunoregulating agents, insecticides, insect repellents, syZigium aromaticum oil, hempseed oil, herring oil, cod-liver keratolytic agents, lactams, metals, metal oxides, mitocides, oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose neuropeptides, non-steroidal anti-inflammatory agents, oxi oils; and essential oils. dizing agents, pediculicides, photodynamic therapy agents, 0098. Some embodiments include silicone oils, such as, retinoids, Sanatives, scabicides, self tanning agents, skin cyclomethicone, polyalkyl siloxane, polyaryl siloxane, poly whitening agents, asoconstrictors, vasodilators, vitamins, alkylaryl siloxane, a polyether siloxane copolymer and a poly Vitamin D derivatives, wound healing agents and wart remov (dimethylsiloxane)-(diphenyl-siloxane) copolymer. In some CS embodiments, the silicone oil is cyclomethicone, cyclotet 0105. According to some embodiments the antibiotic rasiloxane, cyclohexasiloxane, phyenyltrimethicone, Dow agent is selected from the group consisting of beta-lactam corning 246 Fluid (d6+d5) (cyclohexasiloxane & cyclopen antibiotics, aminoglycosides, ansa-type antibiotics, tasiloxane), Dow Corning 244 Fluid (cyclotetrasiloxane), anthraquinones, antibiotic azoles, antibiotic glycopeptides, US 2010/031 0476 A1 Dec. 9, 2010

macrollides, antibiotic nucleosides, antibiotic peptides, anti nocardicin, nogalamycin, novobiocin, octylmonate, olivo biotic polyenes, antibiotic polyethers, quinolones, antibiotic mycin, orthosomycin, oudemansin, oxirapentyn, oxoglau steroids, Sulfonamides, tetracycline, dicarboxylic acids, anti cine methiodide, pactacin, pactamycin, papulacandin, paulo biotic metals including antibiotic metal ions, oxidizing mycin, phaeoramularia fungicide, phenelfamycin, phenyl, agents, Substances that release free radicals and/or active cerulenin, phenylmonate, pholipomycin, pirlimycin, pleuro oxygen, cationic antimicrobial agents, quaternary ammo mutilin, a polylactone derivative, polynitroXin, polyoxin, por nium compounds, biguanides, triguanides, bisbiguanides and firomycin, pradimicin, prenomycin, Prop-2-enylmonate, pro tomycin, Pseudomonas antibiotic, pseudomonic acid, analogs and polymers thereof, naturally occurring antibiotic purpuromycin, pyrinodemin, pyrrolnitrin, pyrrolomycin, compounds, including antibiotic plant oils and antibiotic amino, chloro pentenedioic acid, rapamycin, rebeccamycin, plant extracts and any one of the following antibiotic com resistomycin, reuterin, reveromycin, rhizocticin, roridin, pounds: chlorhexidine acetate, chlorhexidine gluconate and rubiflavin, naphthyridinomycin, Saframycin, Saphenamycin, chlorhexidine hydrochloride, picloxydine, alexidine, poli Sarkomycin, Sarkomycin, Sclopularin, selenomycin, siccanin, hexanide, chlorproguanil hydrochloride, proguanil hydro spartanamicin, spectinomycin, spongistatin, Stravidin, Strep chloride, metformin hydrochloride, phenformin, buformin tolydigin, streptomyces arenae antibiotic complex, streptoni hydrochloride, abomycin, acetomycin, acetoxycyclohexim grin, Streptothricins, streptovitacin, streptozotocine, a strobi ide, acetylnanaomycin, an actinoplanes sp. compound, acti lurin derivative, stubomycin, Sulfamethoxazol-trimethoprim, nopyrone, aflastatin, albacarcin, albacarcin, albofungin, albo Sakamycin, tejeramycin, terpentecin, tetrocarcin, thermoru fungin, alisamycin, alpha-R.S.- bin, thermozymocidin, thiamphenicol, thioaurin, thiolutin, methoxycarbonylbenzylmonate, altromycin, amicetin, thiomarinol, thiomarinol, tirandamycin, tolytoxin, trichoder amycin, amycin demanoyl compound, amycine, amycomy min, trienomycin, trimethoprim, trioxacarcin, tyrissamycin, cin, anandimycin, anisomycin, anthramycin, anti-Syphilis umbrinomycin, unphenelfamycin, urauchimycin, usnic acid, immune Substance, anti-tuberculosis immune Substance, uredolysin, variotin, Vermisporin, Verrucarin, metronidazole, antibiotic from Eschericia coli, antibiotics from Streptomy erythromycin and analogs, salts and derivatives thereof. ces refitineus, anticapsin, antimycin, aplasmomycin, arano 0106. According to some preferred embodiments, the rosin, aranorosinol, arugomycin, ascofuranone, ascomycin, antibiotic agent is a tetracycline. The tetracycline may be ascosin, Aspergillus flavus antibiotic, asukamycin, auranti selected from minocycline and doxycycline. nin, an Aureolic acid antibiotic Substance, aurodox, avilamy 0107 There is thus provided according to some further cin, azidamfenicol, azidimycin, bacillaene, a Bacillus larvae embodiments of the present disclosure, a foamable pharma antibiotic, bactobolin, benanomycin, benzanthrin, benzylmo ceutical carrier for external administration of an unstable nate, bicoZamycin, bravomicin, brodimoprim, butalactin, cal active agent, the carrier including: cimycin, calvatic acid, candiplanecin, carumonam, carzino 0108) 10% to 80% by weight of at least one unstable philin, celesticetin, cepacin, cerulenin, cervinomycin, active agent-compatible (UAAC) solvent, selected from chartreusin, chloramphenicol, chloramphenicol palmitate, the group consisting of an oily emollient, a higher alco chloramphenicol Succinate Sodium, chlorflavonin, chlorobio cin, chlorocarcin, chromomycin, ciclopiroX, ciclopiroX ola hol, a polyol and a polyol alkyl ether, mine, citreamicin, cladosporin, claZamycin, clecarmycin, 0109 10% to 60% by weight of at least one unstable clindamycin, coliformin, collinomycin, copiamycin, coral active agent-compatible (UAAC) hydrophobic solvent; lopyronin, corynecandin, coumermycin, culpin, cuprimyxin, 0110 0.01% to 6% by weight of at least one surface cyclamidomycin, cycloheximide, dactylomycin, danomycin, active agent; and danubomycin, delaminomycin, demethoxyrapamycin, dem 0.111 3% to 25% by weight of a liquefied or com ethylscytophycin, dermadin, desdamethine, dexylosyl-bena pressed gas propellant. nomycin, pseudoaglycone, dihydromocimycin, dihydronan 0112 There is thus provided according to some additional cimycin, diumycin, dnacin, dorrigocin, dynemycin, embodiments of the present disclosure, a foamable pharma dynemycin triacetate, ecteinascidin, efrotomycin, endomy ceutical composition for external administration of an cin, ensanchomycin, equisetin, ericamycin, esperamicin, eth unstable active agent, the composition including: ylmonate, everninomicin, feldamycin, flambamycin, flaven 0113 10% to 80% by weight of at least one unstable Somycin, florfenicol, fluvomycin, fosfomycin, active agent-compatible (UAAC) solvent, selected from foSfonochlorin, fredericamycin, frenolicin, fumagillin, fumi the group consisting of an oily emollient, a higher alco fungin, funginon, fusacandin, fusafungin, gelbecidine, glido hol, a polyol and a polyol alkyl ether, bactin, grahamimycin, granaticin, griseofulvin, griseoviridin, 0114 10% to 60% by weight of at least one unstable grisonomycin, hayumicin, hayumicin, haZymicin, hedamy active agent-compatible (UAAC) hydrophobic solvent; cin, heneicomycin, heptelicidacid, holomycin, humidin, iso 0115 0.01% to 5% by weight of at least one surface hematinic acid, karnatakin, kazusamycin, kristenin, L-dihy active agent; drophenylalanine, a L-isoleucyl-L-2-amino-4-(4-amino-2, 0116 0% to 5% by weight of at least one polymeric 5'-cyclohexadienyl) derivative, lanomycin, leinamycin, lep agent; and tomycin, libanomycin, lincomycin, lomofungin, lysolipin, 0.117 at least one unstable active agent. magnesidin, manumycin, melanomycin, methoxycarbonyl 0118. In some cases, the foamable pharmaceutical com methylmonate, methoxycarbonylethylmonate, methoxycar position includes 3% to 25% by weight of a liquefied or bonylphenylmonate, methyl pseudomonate, methylmonate, compressed gas propellant. microcin, mitomalcin, mocimycin, moenomycin, 0119. According to some further embodiments, the at least monoacetyl cladosporin, monomethyl cladosporin, mupiro one unstable active agent includes an antibiotic agent. cin, mupirocin calcium, mycobacidin, myriocin, myxopyro I0120 Preferably, the disclosed pharmaceutical composi nin, pseudoaglycone, nanaomycin, nancimycin, nargenicin, tion disclosure has the following property: a foam quality of neocarcinostatin, neoenactin, neothramycin, nifurtoinol, at least good up to excellent; and at least one other property US 2010/031 0476 A1 Dec. 9, 2010 selected from: specific gravity in the range of about 0.02 eethyma, yeast skin infections, warts, molluscum contagio gr/mL to about 0.5 gr/mL, a foam texture of a very fine Sum, trauma or injury to the skin, post-operative or post creamy foam consistency to a fine bubble structure consis Surgical skin conditions, scabies, pediculosis, creeping erup tency; a sustainability of more than 95% for at least one tion, eczemas, psoriasis, pityriasis rosea, lichen planus, minute upon release thereof to a surface from an aerosol can: pityriasis rubra pilaris, edematous, erythema multiforme, less than 20% sedimentation following ten minutes of cen erythema nodosum, grannuloma annulare, epidermal trifugation at 3000 g; and compatibility with the at least one necrolysis, Sunburn, photosensitivity, pemphigus, bullous unstable active agent, wherein the compatibility is defined as pemphigoid, dermatitis herpetiformis, keratosis pilaris, cal less than 20% oxidation of the at least one unstable active agent after 72 hours. louses, corns, ichthyosis, skin ulcers, ischemic necrosis, mil 0121. In some cases, the foamable pharmaceutical com iaria, hyperhidrosis, moles, Kaposi's sarcoma, melanoma, position has at least four of the properties. In some other malignant melanoma, basal cell carcinoma, squamous cell cases, the composition has all of the properties. carcinoma, poison ivy, poison oak, contact dermatitis, atopic 0122) There is thus provided according to some additional dermatitis, rosacea, purpura, moniliasis, candidiasis, bald embodiments of the present disclosure, a method for produc ness, alopecia, Behcet's syndrome, cholesteatoma, Dercum ing a foamable pharmaceutical carrier Suitable for external disease, ectodermal dysplasia, gustatory Sweating, nail administration of an unstable active agent, the method includ patella syndrome, lupus, hives, hair loss, Hailey-Hailey dis ing: ease, chemical or thermal skin burns, Scleroderma, aging I0123 testing compatibility of at least one solvent and skin, wrinkles, Sun spots, necrotizing fasciitis, necrotizing the unstable active agent so as to determine at least one myositis, gangrene, Scarring, and vitiligo, chlamydia infec unstable active agent-compatible (UAAC) solvent; and tion, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, 0.124 formulating the foamable pharmaceutical carrier human papillomavirus (HPV), genital warts, bacterial vagi from the at least one unstable active agent-compatible nosis, candidiasis, chancroid, granuloma Inguinale, lym (UAAC) solvent. phogranloma Venereum, mucopurulent cerviciitis (MPC), 0125. In some cases, the testing step includes determining molluscum contagiosum, nongonococcal urethritis (NGU). whether the unstable active agent is at least partially oxidized trichomoniasis, Vulvar disorders, Vulvodynia, Vulvar pain, in the at least one solvent within 72 hours. yeast infection, Vulvar dystrophy, Vulvar intraepithelial neo 0126 There is thus provided, a method for producing a plasia (VIN), contact dermatitis, pelvic inflammation, pharmaceutical composition for external administration of an endometritis, Salpingitis, oophoritis, genital cancer, cancer of unstable active agent, the method including: the cervix, cancer of the Vulva, cancer of the vagina, Vaginal I0127 testing compatibility of at least one solvent and dryness, dyspareunia, anal and rectal disease, anal abscess/ the unstable active agent so as to determine at least one fistula, anal cancer, anal fissure, anal warts, Crohn's disease, unstable active agent-compatible (UAAC) solvent; and hemorrhoids, anal itch, pruritus ani, fecal incontinence, con I0128 formulating the pharmaceutical composition stipation, polyps of the colon and rectum; and wherein the from the at least one unstable active agent-compatible active agent is Suitable for treating the disorder. (UAAC) solvent and the unstable active agent. 0.134. According to Some embodiments, the active agent is 0129. In some cases the unstable active agent is an anti selected from the group consisting of alclometasone dipropi infective agent. The anti-infective agent may be selected from onate, amcinafel, amcinafide, amcinonide, beclomethasone, the group consisting of an antibiotic agent, an antibacterial beclomethasone dipropionate, betamethsone, betamethasone agent, an antifungal agent, an agent that controls yeast, an benzoate, betamethasone dexamethasone-phosphate, dipro antiviral agent and an antiparasitic agent. pionate, betamethasone Valerate, budesonide, chloropred 0130. The pharmaceutical composition may sometimes nisone, chlorprednisone acetate, clescinolone, clobetasol, include a combination of at least two active agents, or some clobetasol propionate, clobetasol Valerate, clobetaSone, clo times three agents. betaSone butyrate, clocortelone, cortisone, cortodoxone, cra 0131 There is thus provided, a method of treating a dis posone butyrate, desonide, desoxymethasone, dexametha order of mammalian Subject, including administering to the Sone, desoxycorticosterone acetate, dichlorisone, diflorasone subject a pharmaceutically effective amount of the foamable diacetate, diflucortolone Valerate, difluorosone diacetate, pharmaceutical composition as described herein. diflurprednate, fluadrenolone, flucetonide, flucloronide, flu 0132. In some cases, the administering includes providing clorolone acetonide, flucortine butylesters, fludroxycortide, the composition to a target site. The target site may be fludrocortisone, flumethasone, flumethasone pivalate, flu selected from the group consisting of the skin, a body cavity, methasone pivalate, flunisolide, fluocinolone, fluocinolone a mucosal Surface, the nose, the mouth, the eye, the ear canal, acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluo the respiratory system, the vagina and the rectum. rometholone, fluosinolone acetonide, fluperolone, flupred 0133. The disorder may be selected from the group con nidene acetate, fluprednisolone hydrocortamate, fluradre sisting of dermatological pain, dermatological inflammation, nolone, fluradrenolone acetonide, flurandrenolone, acne, acne Vulgaris, inflammatory acne, non-inflammatory fluticasone, halcinonide, halobetasol, hydrocortisone, hydro acne, acne fulminans, nodular papulopustular acne, acne con cortisone acetate, hydrocortisone butyrate, hydrocortisone globata, dermatitis, bacterial skin infections, fungal skin cyclopentylpropionate, hydrocortisone Valerate, hydroxyltri infections, viral skin infections, parasitic skin infections, skin amcinolone, medrysone, meprednisone, alpha.-methyl dex neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphan amethasone, methylprednisolone, methylprednisolone gitis, lymphadenitis, erysipelas, cutaneous abscesses, necro acetate, mometaSone furoate, paramethasone, prednisolone, tizing Subcutaneous infections, Scalded skin syndrome, folli prednisone, pregnenolone, progesterone, Spironolactone, tri culitis, furuncles, hidradenitis Suppurativa, carbuncles, amcinolone, triamcinolone acetonide and derivatives, esters paronychial infections, rashes, erythrasma, impetigo, and salts thereof.

US 2010/031 0476 A1 Dec. 9, 2010

tion to the skin, a body Surface, a body cavity or a mucosal ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butyl surface. The carrier is suitable for being formulated in a ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl pharmaceutical composition with at least one active agent. In ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl Some cases, the at least one active agent comprises at least one ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl unstable active agent. ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lau 0180. The term “unstable active agent’ means herein, an ryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 active agent which is oxidized and/or degraded within less methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether, than a day, and in some cases, in less than an hour upon PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, exposure to air, light, skin or water under ambient conditions. PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-50 oleyl ether, 0181. A moiety or phase such as, but not limited to, a PPG-11 stearyl ether. Preferred PPG alky ethers according to molecule and liquid respectively, is deemed herein to be the present disclosure include PPG-15 stearyl ether (also “unstable active agent-compatible (UAAC)' when, upon known as Earlamol E(R), Unichema), PPG-2 butyl ether, PPG contact of the unstable active agent with the moiety or phase, 9-13 butyl ether and PPG-40 butyl ether. PPG alkyl ethers can the agent does not significantly (e.g., more than 20%) oxidize be incorporated in the foamable composition of the present or degrade at room temperature and pressure (RTP) after one disclosure in a concentration between about 1% and about week, preferably three weeks time under ambient conditions. 90%, preferably above 5%, above 10%, above 20%, above 0182 Alternatively, a moiety or phase such as, but not 30% and up to 60% PPG. More preferably between about limited to, a molecule and liquid respectively, is deemed 10% to about 20%. herein to be “unstable active agent-compatible (UAAC) when, upon contact of the unstable active agent with moiety PPG Stearyl Ethers or phase, the agent does not significantly (e.g., preferably 0.192 PPG stearyl ethers function as skin-conditioning more than 5%) oxidize or degrade after one day preferably and penetration agents in cosmetic formulations. one weeks time under ambient conditions. 0193 Polypropylene glycol stearyl ether 15, also known 0183. The identification of a “solvent’, as used herein, is as polyoxypropylene 15 stearyl ether or as “PPG-15', and not intended to characterize the solubilization capabilities of having a CAS Registry No. of 25231-21-4), is a stearyl ether the solvent for any specific active agent or any other compo having about 15 propylene oxide units incorporated in its nent of the foamable composition. Rather, Such information is structure. PPG-15 stearyl ether is a clear liquid, soluble in provided to aid in the identification of materials suitable for mineral oil, isopropyl ethers, cottonseed oil, ethanol, isopro use as a part in the foamable compositions described herein. panol and hexadecyl alcohol, to name a few, and is particu Polypropylene Glycol (PPG) Alkyl Ethers larly useful as a solvent of difficult to formulate ingredients, Such as Sunscreens, aluminum chiorhydrate salts and skin 0184. In the context of the present disclosure, a polypro toners. It is insoluble in water, propylene glycol and glycerin. pylene glycol alkyl ether (PPG alkyl ether) is a liquid, water PPG-15 stearyl ether is an inert and highly stable compound. insoluble propoxylated fatty alcohol, having the molecular 0194 PPG stearyl ether also functions as a coupling agent, formula of RO(CHCHOCH), wherein “R” is a straight allowing, for example, the compatibility of polar and non chained or branched C to C alkyl group; and “n” is in the polar oils with ethanol and perfumes in after shave lotions. It range between 4 and about 50. is chemically stable at extreme pH levels and at the same time 0185 (PPG alkyl ethers), are organic liquids that function saturated, providing excellent shelf life stability. as skin-conditioning agent in pharmaceutical and cosmetic formulations. They possess exceptional emollient effect, side Higher (Fatty) Alcohols by side with enhanced solvency properties, which facilitates solubilization of active agents in a composition comprising a 0.195. In some embodiments of the present disclosure, the PPG alkyl ether. PPG alkyl ethers offer the following advan compositions and carriers comprise one or more higher alco tages when used as a component in the foamable composition hols. These generally exclude “lower alcohols'. The fatty of the present disclosure: alcohols are typically liquid at ambient temperature. 0186. Due to the polypropylene glycol moiety, PPG 0196. Fatty alcohols may defined as follows: alkyl ethers possess certain Surface active properties and The fatty alcohols hereof have a melting point of 30° C. or they assist in the coupling of polar and non-polar oils in less, preferably about 25°C. or less, more preferably about an emulsion formulation; 22° C. or less. 0187 PPG alkyl ethers are non-occlusive; offering a 0197) The unsaturated fatty alcohols hereof are also non long-lasting and velvety feel; volatile. By nonvolatile what is meant is they have a boiling 0188 They are chemically stable at extreme pH condi point at 1.0 atmospheres of at least about 260° C., preferably tions; at least about 275°C., more preferably at least about 300° C. 0189 Excellent solvency properties, particularly with 0198 Suitable fatty alcohols include unsaturated mono difficult to formulate active agents: hydric straight chain fatty alcohols, Saturated branched chain 0190. When combined with certain surfactants, such as fatty alcohols, saturated C8-C12 straight chain fatty alcohols, Brij 72 and Brij 721, PPG alkyl ethers form oleosomes and mixtures thereof. The unsaturated Straight chain fatty and/or liquid crystal structures, which provide long last alcohols will typically have one degree of unsaturation. Di ing moisturization, excellent spreading as well as pro and tri-unsaturated alkenyl chains may be present at low longed hydration properties. levels, preferably less than about 5% by total weight of the (0191 Exemplary PPG alkyl ethers include PPG-2 butyl unsaturated Straight chain fatty alcohol, more preferably less ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl than about 2%, most preferably less than about 1%. ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl 0199 Preferably, the unsaturated straight chain fatty alco ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl hols will have an aliphatic chain size of from C12-C22, more US 2010/031 0476 A1 Dec. 9, 2010 preferably from C12-C18, most preferably from C16-C18. lulose, carboxymethyl cellulose, carboxymethylcellulose Especially preferred alcohols of this type include oleyl alco carboxymethylhydroxyethylcellulose, and cationic cellulo hol and palmitoleic alcohol. ses. Polyethylene glycol, having molecular weight of 1000 or 0200. The branched chain alcohols will typically have ali more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG phatic chain sizes of from C12-C22, preferably C14-C20, 10,000) also have gelling capacity and while they are consid more preferably C16-C18. Exemplary branched chain alco ered herein as “secondary solvents', as detailed herein, they hols for use herein include isostearyl alcohol, octyl dode are also considered polymeric agents. canol, and octyl decanol. Examples of saturated C8-C12 0206 Mixtures of the above polymeric agents are contem straight chain alcohols include octyl alcohol, caprylic alco plated. hol, decyl alcohol, and lauryl alcohol. Furthermore, the 0207. The concentration of the polymeric agent should be higher alcohols may be selected from Straight chain fatty selected so that the composition, after filling into aerosol alcohols, having 6 or more carbon atoms, which are liquid at canisters, is flowable, and can be shaken in the canister. In one ambient temperature, such as, but not limited to Hexanol, or more embodiments, the concentration of the polymeric Octanol, Nonanol, Decanol; branched alcohols, such as: 2 agent is selected Such that the viscosity of the composition, Octanol (Capryl Alcohol). Undecanol (Undecyl Alcohol), 2 prior to filling of the composition into aerosol canisters, is less Butyl Octanol (Isolauryl Alcohol), Tridecyl Alcohol (Isot than 12,000 CPs, and more preferably, less than 10,000 CPs. ridecyl Alcohol), 2 Butyl Decanol, 2 Hexyl Octanol, Isomyri styl Alcohol. 2 Hexyl Decanol, Isocetyl Alcohol, 2 Octyl Surface-Active Agents Decanol, 2 Hexyl Dodecanol, Isostearyl Alcohol, Isooctade canol, Isooleyl Alcohol (unsaturated and branched), 0208. The composition further contains a surface-active Isoarachidyl Alcohol. 2 Decyl Tetradecanol, Isolignoceryl agent. Surface-active agents (also termed 'Surfactants”) Alcohol. 2 Decyl Tetradecanol, 2 Tetradecyl Octadecanol. 2 include any agent linking oil and water in the composition, in Tetradecyl Eicosanol, 2 Hexadecyl Octadecanol, 2 Hexade the form of emulsion. A surfactant's hydrophilic/lipophilic cyl Eicosanol; additionally unsaturated alcohols, such as balance (HLB) describes the emulsifier's affinity toward Erucyl Alcohol, Linoleyl Alcohol, oleyl alcohol may be water or oil. HLB is defined for non-ionic surfactants. The employed. HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with 10 representing an equal balance of both Polymeric Agent characteristics. Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilic Surfactants form oil-in-water 0201 The composition of the present disclosure contains a (ofw) emulsions. The HLB of a blend of two emulsifiers polymeric agent. It has been documented that the presence of equals the weight fraction of emulsifier A times its HLB value a polymeric agent is necessary for the creation of foam, plus the weight fraction of emulsifier B times its HLB value having fine bubble structure, which does not readily collapse (weighted average). In many cases a single Surfactant may upon release from the pressurized aerosol can. The polymeric Suffice. In other cases a combination of two or more Surfac agent serves to stabilize the foam composition and to control tants is desired. Reference to a surfactant in the specification drug residence in the target organ. Preferably, the polymeric can also apply to a combination of Surfactants or a surfactant agent is soluble or readily dispersible in the polyol; or in the system. As will be appreciated by a person skilled in the art mixture of a polyol and an additional solvent. which surfactant or Surfactant system is more appropriate is 0202) Non-limiting examples of polymeric agents that are related to the vehicle and intended purpose. In general terms soluble or readily dispersible in propylene glycol are Hydrox a combination of Surfactants can be significant in producing ypropylcellulose and carbomer (homopolymer of acrylic acid breakable forms of good quality. It has been further discov is crosslinked with anallyl etherpentaerythritol, anallyl ether ered that the generally thought considerations for HLB values of sucrose, or an allyl ether of propylene, such as CarbopolR) for selecting a surfactant or Surfactant combination are not 934, CarbopolR 940, CarbopoR 941, Carbopol.R. 980 and always binding for emulsions and moreover for waterless and Carbopol R 981. Substantially non aqueous carriers the usual guidelines are 0203 Other polymeric agents are suitable for use accord less applicable. For oil based waterless systems HLB values ing to the present disclosure provided that they are soluble or may have little significance other than to indicate the propor readily dispersible in the polyol; or in the mixture of a polyol tion of an ampiphilic molecule that is hydrophobic and there and an additional solvent, on a case by case basis. fore potentially more at home in an oil single phase environ 0204 Exemplary polymeric agents include, in a non-lim ment. Surfactants can play a significant role in foam iting manner, naturally-occurring polymeric materials. Such formation where the foamable formulation is a single phase as locust bean gum, Sodium alginate, sodium caseinate, egg composition. albumin, gelatin agar, carrageenin gum, Sodium alginate, 0209. In selecting a suitable surfactant or surfactant com Xanthan gum, quince seed extract, tragacanth gum, guar gum, bination for use in the Substantially single phase formulations cationic guars, hydroxypropyl guar gum, starch, amine-bear described herein selection relates to a multiple of factors ing polymers such as chitosan; acidic polymers obtainable including but not limited to solubility and miscibility in the from natural sources, such as alginic acid and hyaluronic liquid oil and in the silicone to produce Substantially a single acid; chemically modified starches and the like, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, poly phase; the ability to form foam of quality; the ability to acrylic acid polymers, polymethacrylic acid polymers, poly stabilize the extruded foam; a HLB value which preferably vinyl acetate polymers, polyvinyl chloride polymers, polyvi Suggests potential compatibility with the liquid oil and the nylidene chloride polymers and the like. silicone; and solubility of surfactant in the formulation. 0205 Additional exemplary polymeric agents include 0210. In certain embodiments the surfactant can have semi-synthetic polymeric materials such as cellulose ethers, thickening properties. In certain embodiments the Surfactant Such as methylcellulose, hydroxypropyl cellulose, hydrox can effect the viscosity of the pre foam formulation (PFF). In ypropyl methylcellulose, hydroxyethyl cellulose, hydroxy certain other embodiments the surfactant has little or no propylmethyl cellulose, methylhydroxyethylcellulose, meth effect. The concentration of the Surfactant agent in combina ylhydroxypropylcellulose, hydroxyethylcarboxymethylcel tion with the oil and silicone and other ingredients should be US 2010/031 0476 A1 Dec. 9, 2010 12 selected so that the composition, after filling into aerosol 0215 Preferably, the composition contains a non-ionic canisters, is flowable, and can be shaken in the canister. In one Surfactant. Nonlimiting examples of possible non-ionic Sur or more embodiments, the concentration of the Surfactant factants include a polysorbate, polyoxyethylene (20) sorbitan agent is selected Such that the viscosity of the composition, monostearate, polyoxyethylene (20) Sorbitan monooleate, a prior to filling of the composition into aerosol canisters, is less polyoxyethylene fatty acid ester, Myri 45, Myr 49, Myr 52 than 13,000 CPs, and more preferably, less than 10,000 CPs, and Myr 59; a polyoxyethylene alkyl ether, polyoxyethylene preferably below about 9000, more preferably below about cetyl ether, polyoxyethylene palmityl ether, polyethylene 6000 cps. In one or more embodiments average bubble size of oxide hexadecyl ether, polyethylene glycol cetyl ether, Ste the resultant foam should be below about 200 microns, pref areths such as steareth 2, brij21, brij721, brij 38, brij 52, brij erably below 150 and more preferably below 100 microns; In 56 and bri W1, a sucrose ester, a partial ester of sorbitol and one or more embodiments foam density is below about 0.2 its anhydrides, Sorbitan monolaurate, Sorbitan monolaurate, a preferably below about 0.1 g/ml. In one or more embodiments monoglyceride, a fatty acid ester of glycerol, a mono, di or hardness of the resultant foam is in the range of about 5 to triglyceride of Stearic acid, a mono, di or triglyceride of about 35. palmitic acid, a diglyceride, isoceteth-20 and mono-, di- and 0211. According to one or more embodiments the compo tri-esters of Sucrose with fatty acids. In certain embodiments, sition contains a single Surface active agent having an HLB Suitable Sucrose esters include those having high monoester value between about 2 and 9, or more than one surface active content, which have higher HLB values. However, sorbitan agent and the weighted average of their HLB values is esters are not used alone as primary Surfactants. In an embodi between about 2 and about 9. ment if present Sorbitan esters are used in combination with 0212. According to one or more embodiments the compo one or more primary Surfactants and functions as a secondary sition contains a single Surface active agent having an HLB or co-surfactant. value between about 7 and 14, (preferably about 7 to about 0216. In one or more embodiments the surfactant is 12) or more than one Surface active agent and the weighted selected to produce a foam of quality being of least of about average of their HLB values is between about 7 and about 14 good quality foam and preferably of excellent quality foam. (preferably about 7 to about 12). In one or more embodiments the Surfactant includes, a fatty 0213. According to one or more other embodiments the acid ester of glycerol. Such as a mono, di or trifatty ester of composition contains a single Surface active agent having an Stearic acid or palmitic acid or arachidic acid or beheneic HLB value between about 9 and about 19, or more than one acid. In one or more embodiments the Surfactant is used on its surface active agent and the weighted average of their HLB own with the oil. In certain other embodiments the surfactant values is between about 9 and about 19. is used in combination with one or more other Surfactants, 0214. In a waterless or substantially waterless environ such as, those listed below. In an embodiment the combina ment a wide range of HLB values may be suitable. In one or tion is, for example, glycerol monostearate and PEG 100 more embodiments the HLB may not play a role in a single Stearate. Other similar combinations are readily envisaged. phase system 0217 Glycerol Fatty Acid Esters

Fatty acid Ester Function Solubility (main) Comments Glyceryl Behenate Thickener, Practically Beheneic (C22) Nottested lubricant insoluble in oil and water Glyceryl Non ionic Soluble in oil Oleic (double Fairly Good monooleate Sufactant and practically bond in side Foam with insoluble in chain (C18) mineral oil and Water silicone Glyceryl Non ionic Soluble in Stearic (C18) Good - nonOStearate emulsifying mineral oil and Excellent Foam (GMS) agent practically with mineral oil insoluble in and silicone oil Water even though GMS and other fatty acid monoesters are not efficient emulsifiers. Glyceryl Sustained Practically Mixture of Excellent Foam Palmitostearate release, insoluble in mono (~<17%), with mineral oil lubricant mineral oil and di, and and silicone oil Water triglycerides of even though C16 and C18 GMS and other fatty acids fatty acid monoesters are not efficient emulsifiers US 2010/031 0476 A1 Dec. 9, 2010

0218. In an embodiment the surfactant is an ether for premixing, nor high rate of shear nor neutralisation. Sepigel example polyoxyethylene (26) glycerol ether. 305 can be used to emulsify all types of oil phase without 0219. In certain embodiments, surfactants are selected heating, producing gel-cream with a rich, silky texture that which can provide a close packed Surfactant layer. To achieve are easy to apply and rapidly absorbed by the skin. Such objectives combinations of at least two Surfactants are 0225. More exemplary stabilizing surfactants which may selected. Preferably, they should be complex emulgators and be suitable for use in the present disclosure are found below. more preferably they should both be of a similar molecular 0226 PEG-Fatty Acid Monoester Surfactants, such as: type; for example, a pair of ethers, like Steareth 2 and Steareth 21, or a pair of esters, for example, PEG-40 stearate and polysorbate 80. Ideally, the surfactants can be ethers. In cer tain circumstances POE esters cannot be used and a combi Chemical name Product example name HLB nation of Sorbitan laurate and Sorbitan Stearate or a combina PEG-30 Stearate Myri 51 >10 tion of Sucrose Stearic acid ester mixtures and Sodium laurate PEG-40 laurate Crodet LAO (Croda) 17.9 may be used. All these combinations due to their versatility PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-45 Stearate Nikkol MYS-45 (Nikko) 18 and strength may also be used satisfactorily and effectively PEG-50 Stearate Myri 53 >10 with etherformulations, although the amounts and proportion PEG-1OO Stearate Myri 59, Arlacel 165 (ICI) 19 may be varied according to the formulation and its objectives as will be appreciated by a man of the art. 0220. It has been discovered also that by using a deriva 0227 PEG-Fatty Acid Diester Surfactants, such as: tized hydrophilic polymer with hydrophobic alkyl moieties as a polymeric emulsifier Such as pemulen it is possible to sta bilize the emulsion better about or at the region of phase Chemical name Product example name HLB reversal tension. Other types of derivatized polymers like PEG-4 dilaurate Mapeg.RTM. 200 DL (PPG), 7 silicone copolymers, derivatized Starch Aluminum Starch Kessco RTMPEG 20ODL Octenylsuccinate (ASOS)/DRY-FLO AF Starch, and (Stepan), LIPOPEG 2-DL (Lipo derivatized dexrin may also a similar stabilizing effect. Chem.) 0221) A series of dextrin derivative surfactants prepared PEG-4 distearate Kessco RTM. 200 DS 5 by the reaction of the propylene glycol polyglucosides with a (Stepan.Sub) PEG-32 dioleate Kessco RTMPEG 1540 DO 15 hydrophobic oxirane-containing material of the glycidyl (Stepan) ether are highly biodegradable. Hong-Rong Wang and Keng PEG-400 dioleate Cithrol 4DO series (Croda) >10 Ming Chen, Colloids and Surfaces A: Physicochemical and PEG-400 disterate Cithrol 4DS series (Croda) >10 Engineering Aspects Volume 281, Issues 1-3, 15 Jun. 2006, PEG-20 glyceryl oleate Tagat. RTM. O (Goldschmidt) >10 Pages 190-193. 0222 Non-limiting examples of non-ionic surfactants that 0228 Transesterification Products of Oils and Alcohols, have HLB of about 7 to about 12 include steareth 2 (HLB-4. Such as: 9); glyceryl monostearate/PEG 100 stearate (AV HLB-11.2): stearate Laureth 4 (HLB-9.7) and cetomacrogol ether (e.g., polyethylene glycol 1000 monocetyl ether). 0223 Non-limiting examples of preferred surfactants, Chemical name Product example name HLB which have a HLB of 4-19 are set out in the Table below: PEG-30 castor oil Emalex C-30 (Nihon Emulsion) 11 PEG-40 hydrogenated castor Cremophor RH 40 (BASF), 13 oil Croduret (Croda), Emulgin HRE 40 (Henkel) Surfactant HLB steareth 2 ~4.9 0229 Polyglycerized Fatty Acids, such as: glyceryl monostearate/PEG 100 stearate Av -11.2 Glyceryl Stearate ~4 Steareth-21 -15.5 peg 40 stearate ~16.9 polysorbate 80 -15 Chemical name Product example name LB sorbitan Stearate ~4.7 Polyglyceryl-6 dioleate Caprol.RTM. 6G20 (ABITEC): 8.5 laureth 4 --97 PGO-62 (Calgene), PLUROL Sorbitan monooleate (span 80) ~4.3 OLEIQUE CC 497 ceteareth 20 -15.7 (Gattefosse)Hodag steareth 20 -15.3 ceteth 20 -15.7 Macrogol Cetostearyl Ether -15.7 ceteth 2 (Lipocol C-2) --53 0230 PEG-Sorbitan Fatty Acid Esters, such as: PEG-30 Dipolyhydroxystearate --55 sucrose distearate (Sisterna SP30) -6 polyoxyethylene (100) stearate ~18.8 Chemical name Product example name HLB 0224. Another component of the formulations of the PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 17 (Croda), DACOL MLS 20 present disclosure is Sepigel 305. Sepigel 305 comprises (Condea) Polyacrylamide and C13-14 Isoparaffin and Laureth-7. It acts PEG-20 Sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 as a Surfactant and as a thickening and emulsifying agent, and Monopalmitate (Croda) comes in a liquid, very easy to handle form. It requires neither US 2010/031 0476 A1 Dec. 9, 2010 14

nations of sucrose esters, such as Surphope 1816/Surphope -continued 1807; combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span 60; combinations of sucrose esters and Chemical name Product example name HLB sorbitan esters, such as Surphope 1811 and Span 60; combi PEG-20 Sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 nations of liquid polysorbate detergents and PEG com nonOStearate (Croda) pounds, such as Tween 80/PEG-40 stearate; methyl glucaso PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), Crillet 4 15 sequistearate; polymeric emulsifiers, such as Permulen (TR1 (Croda) or TR2); liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1), Nikomulese (41) and Montanov (68) and 0231 Polyethylene Glycol Alkyl Ethers, such as: the like. 0236. In certain embodiments the surfactant is preferably one or more of the following: a combination of steareth-2 and steareth-21 on their own or in combination with glyceryl Chemical name Product example name HLB monostearate (GMS); in certain other embodiments the sur PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 factant is a combination of polysorbate 80 and PEG-40 stear PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) <10 ate. In certain other embodiments the Surfactant is a combi PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij 12 nation of glyceryl monostearate/PEG 100 stearate. In certain 96/97 (Atlas/ICI) other embodiments the surfactant is a combination of two or PEG-20 oleyl ether oleth-20 Volpo 20 (Croda), Brij 15 more of stearate 21, PEG 40 stearate, and polysorbate 80. In 98/99 (Atlas/ICI) certain other embodiments the Surfactant is a combination of PEG-4 lauryl ether laureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35 (Atlas/ICI) 17 two or more of laureth 4, span80, and polysorbate 80. In PEG-10 stearyl ether Brij 76 (ICI) 12 certain other embodiments the Surfactant is a combination of PEG-2 cetyl ether Brij 52 (ICI) 5.3 two or more of GMS and ceteareth. In certain other embodi ments the Surfactant is a combination of two or more of steareth 21, ceteareth 20, ceteth 2 and laureth 4. In certain 0232 Sugar Ester Surfactants, such as: other embodiments the Surfactant is a combination of cet eareth 20 and polysorbate 40 stearate. In certain other embodiments the Surfactant is a combination of span 60 and Chemical name Product example name HLB GMS. In certain other embodiments the surfactant is a com bination of two or all of PEG 40 stearate, sorbitanstearate and Sucrose distearate Sisterna SP50, Surfope 1811 11 polysorbate 60 0237. In certain other embodiments the surfactant is one or 0233 Sorbitan Fatty Acid Ester Surfactants, such as: more of Sucrose Stearic acid esters, Sorbitan laureth, and Sor bitan Stearate. 0238. Without being bound by any particular theory or mode of operation, it is believed that the use of non-ionic Chemical name Product example name HLB Surfactants with significant hydrophobic and hydrophilic Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 components, increase the emulsifier or foam stabilization (Croda), Arlacel 20 (ICI) characteristics of the composition. Similarly, without being Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 bound by any particular theory or mode of operation, using (Croda), Nikkol SP-10 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 combinations of surfactants with high and low HLB's to (Croda), Crill 50 (Croda) provide a relatively close packed surfactant layer may Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7 strengthen the formulation. (Croda), Nikkol SS-10 (Nikko) 0239. In one or more embodiments the stability of the composition can be improved when a combination of at least 0234. In one or more embodiments the surface active one non-ionic surfactant having HLB of less than 9 and at agent is a complex emulgator in which the combination of least one non-ionic Surfactant having HLB of equal or more two or more Surface active agents can be more effective than than 9 is employed. The ratio between the at least one non a single Surfactant and provides a more stable formulation or ionic surfactant having HLB of less than 9 and the at least one improved foam quality than a single Surfactant. For example non-ionic Surfactant having HLB of equal or more than 9, is and by way of non-limiting explanation it has been found that between 1:8 and 8:1, or at a ratio of 4:1 to 1:4. The resultant by choosing say two surfactants, one hydrophobic and the HLB of such a blend of at least two emulsifiers is preferably other hydrophilic the combination can produce a more stable between about 9 and about 14. emulsion than a single surfactant. Preferably, the complex 0240 Thus, in an exemplary embodiment, a combination emulgator comprises a combination of Surfactants wherein of at least one non-ionic surfactant having HLB of less than 9 there is a difference of about 4 or more units between the HLB and at least one non-ionic Surfactant having HLB of equal or values of the two surfactants or there is a significant differ more than 9 is employed, at a ratio of between 1:8 and 8:1, or ence in the chemical nature or structure of the two or more at a ratio of 4:1 to 1:4, wherein the HLB of the combination of Surfactants. emulsifiers is preferably between about 5 and about 18. 0235 Specific non limiting examples of surfactant sys 0241. In certain cases, the Surface active agent is selected tems are, combinations of polyoxyethylene alkyl ethers. Such from the group of cationic, Zwitterionic, amphoteric and as Brij 59/Brij 10; Brij 52/Brij 10; Steareth 2/Steareth 20; ampholytic Surfactants, such as sodium methyl cocoyl tau Steareth 2/Steareth 21 (Brij 72/Brij 721); combinations of rate, Sodium methyl oleoyl taurate, sodium lauryl Sulfate, polyoxyethylene stearates such as Myri 52/Myri 59; combi triethanolamine lauryl sulfate and betaines. US 2010/031 0476 A1 Dec. 9, 2010

0242. Many amphiphilic molecules can show lyotropic Surface active agent comprises a combination of a non-ionic liquid-crystalline phase sequences depending on the Volume Surfactant and an ionic Surfactant, at a ratio of between 1:1 balances between the hydrophilic part and hydrophobic part. and 20:1 These structures are formed through the micro-phase segre 0251. In one or more embodiments, a combination of a gation of two Many amphiphilic molecules can show lyotro non-ionic Surfactant and an ionic Surfactant (Such as sodium pic liquid-crystalline phase sequences depending on the Vol lauryl Sulphate and cocamidopropylbetaine) is employed, at a ume balances between the hydrophilic part and hydrophobic part. These structures are formed through the micro-phase ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1; for segregation of two incompatible components on a nanometer example, about 1:1, about 4:1, about 8:1, about 12:1, about scale. Soap is an everyday example of a lyotropic liquid 16:1 and about 20:1 or at a ratio of 4:1 to 10:1, for example, crystal. Certain types of Surfactants tend to form lyotropic about 4:1, about 6:1, about 8:1 and about 10:1. liquid crystals in emulsions interface (oil-in-water) and exert 0252 For foams in selecting a suitable surfactant or com a stabilizing effect bination thereof it should be borne in mind that the upper 0243 In one or more embodiments the surfactant is a amount of surfactant that may be used may be limited by the Surfactant or Surfactant combination is capable of or which shakability of the composition. If the Surfactant is non liquid, tends to form liquid crystals. Surfactants which tend to form it can make the formulation to viscous or solid. Subject to its liquid crystals may improve the quality of foams. Non limit miscibily Solid Surfactants may be added first, and may ing examples of surfactants with postulated tendency to form require gentle warming and then cooling before being com interfacial liquid crystals are: phospholipids, alkyl gluco bined with the other ingredients. In general terms, as the sides, Sucrose esters, Sorbitan esters. amount of non-liquid Surfactant is increased the shakability 0244. In one or more embodiments the at least one surface of the formulation reduces until a limitation point is reached active agent is liquid. Moreover for the purposes of formulat where the formulation can become non shakable and unsuit ing with liquid ethers a liquid Surfactant is preferred able. Thus in one embodiment, any effective amount of sur factant may be used provided the formulation remains shak 0245. In one or more embodiments the liquid surfactant is able. In other certain limited embodiments the upper limit for a polysorbate, preferably polysorbate 80 or 60. foamable formulations may be determined by flowability 0246. In one or more embodiments the at least one surface such that any effective amount can be used provided the active agent is solid, semi Solid or waxy. In a further embodi formulation is sufficiently flowable to be able to flow through ment they are soluble in oil and in another embodiment have an actuator valve and be released and still expand to form a a HLB of less than about 12. good quality foam. This may be due without being bound by 0247. It should be noted that HLB values may not be so any theory to one or more of a number of factors such as the applicable to non ionic Surfactants, for example, with liquid Viscosity, the softness, the lack of crystals, the pseudoplastic crystals or with silicones. Also HLB values may be of lesser or semi pseudo plastic nature of the composition and the significance in a waterless or Substantially non-aqueous envi dissolution of the propellant into the composition. rOnment. 0253. In certain embodiments the amount of surfactant or 0248. In one or more embodiments the surfactant can be, a combination of surfactants is between about 0.05% to about Surfactant system comprising of a Surfactant and a co Surfac 20%; between about 0.05% to about 15%. or between about tant, a waxy emulsifier, a liquid crystal emulsifier, an emul 0.05% to about 10%. In a preferred embodiment the concen sifier which is solid or semi solid at room temperature and tration of surface active agent is between about 0.2% and pressure, or combinations of two or more agents in an appro about 8%. In a more preferred embodiments the concentra priate proportion as will be appreciated a person skilled in the tion of surface active agent is between about 1% and about 6% art. Where a solidorsemi solid emulsifier combination is used or between about 1% and about 4%. it can also comprise a solid or semi solid emulsifier and a 0254. In some embodiments, it is desirable that the surface liquid emulsifier. In a preferred embodiment at least one active agent does not contain a polyoxyethylene (POE) moi Surfactant is a liquid. ety, such as polysorbate surfactants, POE fatty acid esters, 0249. In one or more embodiments, the surface-active and POE alkyl ethers, because the active agent is incompat agent includes at least one non-ionic Surfactant. Ionic Surfac ible with Such surface active agents. For example, the active tants are known to be irritants. Therefore, non-ionic Surfac agent pimecrolimus is not stable the presence of POE moi tants are preferred in applications including sensitive tissue eties, yet benefits greatly from the use of dicarboxylic esters Such as found in most mucosal tissues, especially when they as penetration enhancers. In Such cases, alternative Surface are infected or inflamed. Non-ionic Surfactants alone can active agents are employed. In an exemplary manner, POE provide formulations and foams of good or excellent quality free surfactants include non-ethoxylated Sorbitan esters. Such in the carriers and compositions of the present disclosure. as Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan 0250 Thus, in a preferred embodiment, the surface active tristearate, Sorbitan monooleate, Sorbitan trioleate, Sorbitan agent, the composition contains a non-ionic Surfactant. In monolaurate and Sorbitan sesquioleate; glycerol fatty acid another preferred embodiment the composition includes a esters, such as glycerol monostearate and glycerol mixture of non-ionic Surfactants as the sole Surface active monooleate; mono-, di- and tri-esters of Sucrose with fatty agent. Yet, in additional embodiments, the foamable compo acids (sucrose esters). Sucrose Stearate. Sucrose distearate sition includes a mixture of at least one non-ionic Surfactant Sucrose palmitate and Sucrose laurate; and alkyl polyglyco and at least one ionic Surfactant in a ratio in the range of about sides, such as lauryl diglucoside. 100:1 to 6:1. In one or more embodiments, the non-ionic to 0255. In one or more embodiments, the surface-active ionic Surfactant ratio is greater than about 6:1, or greater than agent includes mono-, di- and tri-esters of Sucrose with fatty about 8:1; or greater than about 14:1, or greater than about acids (sucrose esters), prepared from Sucrose and esters of 16:1, or greater than about 20:1. In further embodiments, fatty acids or by extraction from sucro-glycerides. Suitable US 2010/031 0476 A1 Dec. 9, 2010

Sucrose esters include those having high monoester content, 0268 cosmetic scrub materials, including, for example which have higher HLB values. meals of Strawberry seeds, raspberry seeds, apricot seeds, 0256 In one or more preferred embodiments of the Sweet almond, cranberry seeds; and pigments, which are present disclosure the Surfactant includes at least one Surfac insoluble in the foamable composition. tant selected from a polyoxyethylene fatty ether, a polyoxy ethylene fatty ester, a carbohydrate ester and a Sucrose ester. Hydrophobic Solvent 0257. In one or more embodiments nonlimiting examples of non-ionic Surfactants include Steareth-2, Steareth-20, Ste 0269 Optionally, the foamable carrier further contains at areth-21, ceteareth 2, PEG-100 stearyl ether, cetearylgluco least one hydrophobic solvent. The identification of a “hydro side, Methy Glucose Sesquistearate, Sorbitan monostearate, phobic solvent, as used herein, is not intended to character GMS NE and span 20. ize the solubilization capabilities of the solvent for any spe 0258. In one or more embodiments non limiting other cific active agent or any other component of the foamable examples of surfactant combinations are glyceryl Stearate and composition. Rather, such information is provided to aid in PEG 100 stearate and laureth4; Steareth 2, PEG 100 searate the identification of materials suitable for use as a part in the and laureth4; and cetearyl glucoside and cetearyl alcohol. foamable compositions described herein. 0259. In an embodiment the surfactant containing formu 0270. A “hydrophobic solvent as used herein refers to a lations are further boosted by a foam adjuvant for example material having solubility in distilled water at ambient tem Stearyl alcohol. perature of less than about 1 gm per 100 mL, more preferable 0260 A nonlimiting example of a combination of surfac tants having a weighted average of their HLB values of 11 is less than about 0.5gm per 100 mL, and most preferably less Glyceryl Stearate and PEG-100 Stearate (for example trade than about 0.1 gm per 100 mL. name “simulsol 165' from Sepic). 0271 In one or more embodiments, the hydrophobic organic carrier is an oil. Such as mineral oil, isopropyl palmi Solid Matter Agents tate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyl lactate, 0261 According to an embodiment of the present disclo cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alco Sure, the at least one active agent comprises Solid matter or hol, cetyl acetate, phenyl trimethicone, glyceryl oleate, toco particulate matter i.e., material that is not soluble in the liquid pheryl linoleate, wheat germ glycerides, arachidyl propi carrier composition of the foamable composition. For defini onate, myristyl lactate, decyl oleate, propylene glycol tion purposes, Solid matter shall mean material that is not ricinoleate, isopropyl lanolate, pentaerythrity1 tetrastearate, soluble in the foamable composition more than 10% of the neopentylglycol dicaprylate/dicaprate, isononyl concentration intended to be included in said foamable com isononanoate, isotridecyl isononanoate, myristyl myristate, position. The concentration of the solid matter in the foam triisocetyl citrate, octyl dodecanol, unsaturated or polyun able composition is from about 0% to about 20% w/w. In one saturated oils, such as olive oil, corn oil, Soybean oil, canola or more embodiments, the concentration of solid matter in the oil, cottonseed oil, coconut oil, sesame oil, Sunflower oil, composition is from about 2% to about 16% w/w. borage seed oil, SyZigium aromaticum oil, hempseed oil, 0262 By way of non-limiting examples, the following herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ classes of Solid matter Substances are presented: oil, evening primrose oils; essential oils; and silicone oils, 0263 Metallic oxides, such as titanium dioxide, zinc Such as cyclomethicone, polyalkyl siloxanes, polyaryl silox oxide, zirconium oxide, iron oxide. Preferably, as used in the anes, polyalkylaryl siloxanes and polyether siloxane copoly present disclosure, titanium dioxide has an average primary mers, and poly(dimethylsiloxane)-(diphenyl-siloxane) particle size of from about 15 nm to about 100 nm, Zinc oxide copolymers. having an average primary particle size of from about 15 nm 0272. One class of hydrophobic solvents includes polyun to about 150 nm, Zirconium oxide having an average primary saturated oils, containing omega-3 and omega-6 fatty acids, particle size of from about 15 nm to about 150 nm, iron oxide which are know to possess therapeutic properties through having an average primary particle size of from about 15 nm different modes of action. Examples of Such polyunsaturated to about 500 nm, and mixtures thereof. In one embodiment fatty acids are linoleic and linolenic acid, gamma-linoleic the metal oxides are present in the amount of from about 0.1% acid (GLA), eicosapentaenoic acid (EPA) and docosa to about 20%, preferably from about 0.5% to about 16%, hexaenoic acid (DHA). Thus, in one preferred embodiment of more preferably from about 1% to about 10%, of the compo the present disclosure the at least one hydrophobic solvent sition. In yet another embodiment, such solids are micronized comprises at least 6% of an oil selected from omega-3 oil, to form particles having primary size of less than 15 nm. omega-6 oil, and mixtures thereof. 0264. Silicon containing solid matter includes silicone 0273 Another preferred class of hydrophobic solvents oxide, also termed “silica”, “fumed silica” and “silica gel', a comprises the essential oils, which are considered “therapeu white or colorless insoluble solid (SiO2); and talc, which is tic oils, which contain active biologically occurring mol fine grained mineral consisting of hydrated magnesium sili ecules and, upon topical application, exert a therapeutic Cate, effect. Examples of such oils are rosehip oil, which contain 0265 Carbon, for example in the form of amorphous car retinoids and is known to reduce acne and post-acne Scars, tea bon or graphite; tree oil, which possesses anti-microbial activity including 0266 Oxidizing agents. Such as benzoyl peroxide, cal antibacterial, antifungal and antiviral properties. Other cium and magnesium hypochlorite; examples of essential oils are basil, camphor, cardamom, 0267 Metallic Silver, in small particles, including nanoc carrot, citronella, clary sage, clove, cypress, frankincense, rystalline silver, which is used for antibacterial and wound ginger, grapefruit, hyssop, jasmine, lavender, lemon, manda healing purposes; other metal particles and mineral particles; rin, marjoram, myrrh, neroli, nutmeg, petitgrain, Sage, tan US 2010/031 0476 A1 Dec. 9, 2010 gerine, Vanilla, Verbena, as well as any other therapeutically is oleyl alcohol, Stearyl alcohol, or myristyl alcohol. In some beneficial oil known in the art of herbal medication. embodiments, the foam adjuvant is cocoglycerides. 0277. In one or more embodiments of the present disclo Emollients Sure, the foam adjuvant agent includes fatty acids having 16 or more carbons in their carbon chain, such as hexadecanoic 0274. A further preferred class of solvents are “emol acid (C16) stearic acid (C18), arachidic acid (C20), behenic lients' that have a softening, refatting, or soothing effect, acid (C22), octacosanoic acid (C28), as well as fatty acids especially when applied to body areas, such as the skin and with longer carbon chains (up to C50), or mixtures thereof. As mucosal Surfaces. Emollients are not necessarily hydropho for fatty alcohols, the amount of fatty acids required to Sup bic. Without derogating the generality of this definition, port the foam system is inversely related to the length of its examples of suitable emollients for use include but are not carbon chain. limited to mineral oil, lanolin oil, coconut oil, cocoa butter, 0278. Optionally, the carbon atom chain of the fatty alco olive oil, aloe Vera extract, jojoba oil, castor oil, fatty acids, hol or the fatty acid may have at least one double bond. A fatty alcohols, diisopropyl adipate, hydroxybenzoate esters, further class of foam adjuvantagent includes a branched fatty benzoic acid esters of C9 to C15 alcohols, isononyl iso alcohol or fatty acid. The carbon chain of the fatty acid or fatty nonanoate, isopropyl myristate, silicone oils, polyethers, C12 alcohol also can be substituted with a hydroxyl group, Such as to C15 alkyl benzoates, oleic acid, stearic fatty acid, cetyl 12-hydroxy Stearic acid. alcohols, hexadecyl alcohol, dimethyl polysiloxane, polyox Polyol ypropylene cetyl ether, polyoxypropylene butyl ether, hexy leneglycol, propylene glycol, isostearic acid derivatives, iso 0279. In an embodiment of the present disclosure, the propyl palmitate, isopropyl isostearate, diisopropyl adipate, Solvent is a polyol. A polyol is an organic Substance that diisopropyl dimerate, maleated Soybean oil, octyl palmitate, contains at least two hydroxy groups in its molecular struc cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated ture. lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl 0280. In one or more embodiments, the foamable carrier oleate, tocopheryl linoleate, wheat germ glycerides, contains at least one diol (a compound that contains two arachidyl propionate, myristyl lactate, decyl oleate, propy hydroxy groups in its molecular structure). Examples of diols lene glycol ricinoleate, isopropyllanolate, pentaerythrity1 tet include propylene glycol (e.g., 1,2-propylene glycol and 1.3- rastearate, neopentylglycol dicaprylate/dicaprate, isononyl propylene glycol), butanediol (e.g., 1.2-butanediol. 1,3-bu isononanoate, isotridecyl isononanoate, myristyl myristate, tanediol. 2,3-butanediol and 1,4-butanediol), butanediol triisocetyl citrate, octyl dodecanol. Sucrose esters of fatty (e.g., 1,3-butanediol and 1,4-butenediol), butynediol, pen acids, octyl hydroxy Stearate and, and derivatives, esters, salts tanediol (e.g., pentane-1,2-diol, pentane-1,3-diol, pentane-1, and mixtures thereof. Examples of other suitable emollients 4-diol, pentane-1,5-diol, pentane-2,3-diol and pentane-2,4- may be found in the Cosmetic Bench Reference, pp. 1.19-1. diol), hexanediol (e.g., hexane-1,6-diol hexane-2,3-diol and 22 (1996) and in similar publications. In an embodiment of hexane-2.56-diol), octanediol (e.g., 1.8-Octanediol), neopen the present disclosure, the oily solvent component is an emol tylglycol, 2-methyl-1,3-propanediol, diethylene glycol, tri lient. ethylene glycol, tetraethylene glycol, dipropylene glycol and 0275. In some embodiments, the emollients used in the dibutylene glycol. present disclosure are oily emollients. Non-limiting 0281. In one or more embodiments, the foamable carrier examples of oily emollients include Cetearyl Octanoate, contains at least one triol (a compound that contains three Cyclomethicone, PPG-15 Stearyl Ether, Propylene glycol, hydroxy groups in its molecular structure), such as glycerin, Octyldodecanol, Glycerol, Diisopropyl adipate, and isos butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol. tearic acid. 0282. In one or more embodiments, the polyol is a mixture of polyols. In one or more embodiments, the mixture of polyols contains at least one diol and at least one triol. Foam Adjuvant According to certain embodiments the ratio between the diol 0276 Optionally, a foam adjuvant is included in the foam and triol is between 9:1 and 1:1. able carriers of the present disclosure to increase the foaming 0283. In one or more embodiments, part of mixture of capacity of Surfactants and/or to stabilize the foam. In one or polyols is a saccharide. Exemplary saccharides include, but more embodiments of the present disclosure, the foam adju are not limited to monosaccharide, disaccharides, oligosac vant agent includes fatty alcohols having 15 or more carbons charides and Sugar alcohols. in their carbon chain, Such as cetyl alcohol and Stearyl alcohol 0284. A monosaccharide is a simple Sugar that cannot be (or mixtures thereof). Other examples of fatty alcohols are hydrolysed to smaller units. Empirical formula is (CHO), arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacon and range in size from trioses (n-3) to heptoses (n=7). Exem tanol (C30), as well as alcohols with longer carbon chains (up plary monosaccharide compounds are ribose, glucose, fruc to C50). Fatty alcohols, derived from beeswax and including tose and galactose. a mixture of alcohols, a majority of which has at least 20 0285 Disaccharides are made up of two monosaccharides carbonatoms in their carbon chain, are especially well Suited joined together, Such as Sucrose, maltose and lactose. as foam adjuvant agents. The amount of the fatty alcohol 0286 A sugar alcohol (also known as a polyol, polyhydric required to Support the foam system is inversely related to the alcohol, or polyalcohol) is a hydrogenated form of saccha length of its carbon chains. Foam adjuvants, as defined herein ride, whose carbonyl group (aldehyde or ketone, reducing are also useful in facilitating improved spreadability and Sugar) has been reduced to a primary or secondary hydroxyl absorption of the composition. In some embodiments, a foam group. They are commonly used for replacing Sucrose in adjuvant is a fatty alcohol having between 14 and 18 carbons foodstuffs, often in combination with high intensity artificial in its carbon chain. In some embodiments, the foam adjuvant Sweeteners to counter the low Sweetness. Some exemplary US 2010/031 0476 A1 Dec. 9, 2010

Sugar alcohols, which are Suitable for use according to the permeability across the skin, as Suggested, for example, in present disclosure are mannitol, Sorbitol, Xylitol, maltitol, EurJ Pharm Biopharm. 1998 November; 46(3):265-71. lactitol. (Maltitol and lactitol are not completely hydroge 0291 Thus, in one or more embodiments, the foamable nated compounds—they are a monosaccharide combined carrier contains (1) at least one solvent, selected from a polyol with a polyhydric alcohol). Mixtures of polyols, including (1) (selected from a diol and a triol) and PEG, and (2) at least one at least one polyol selected from a diol and a triol; and (2) a secondary solvent. saccharide are contemplated within the scope of the present 0292. In one or more embodiments, the foamable carrier disclosure. contains (1) a mixture of at least two polyols; and (2) at least one secondary solvent. In additional embodiments, the foam Polyethylene Glycol able carrier contains a mixture of at least one polyol and at 0287. In an embodiment of the present disclosure, the least one PEG, yet in other embodiments the foamable carrier Solvent consists of a polymerized ethylene glycol, namely contains (1) a mixture of at least one polyol and at least one polyethylene glycol, which is also termed “PEG'. Exemplary PEG and (2) at least one secondary solvent. PEGs are provided in the following table. 0293 According to certain embodiments the ratio between the polyol and/or PEG and the secondary solvent is between 9:1 and 1:1. 0294. In certain embodiments, the polyol is selected from Composition AV. Molecular weight Appearance Melting point (C.) the group consisting of propylene glycol, hexylene glycoland PEG 200 190-210 Oily liquid glycerin (and mixtures thereof); and the secondary solvent is PEG 300 285-315 Oily liquid selected from the group consisting of dimethyl isosorbide, PEG 400 380-420 Oily liquid diethylene glycol monoethyl ether, a liquid polyethylene gly PEG 600 570-630 Oily liquid 17-22 col and glycofurol. PEG 1 OOO 950-1OSO Solid 35-40 PEG 4OOO 3800-44OO Solid 53-58 0295. In certain embodiments, the foamable carrier con PEG 6000 5600-64OO Solid SS-60 tains (1) at least one polyol; and (2) dimethyl isosorbide. PEG 8000 7SOO-85OO Solid 58-65 Substantially Alcohol Free 0288 Thus, in an embodiment of the present disclosure, 0296 Lower or short chain alcohols, having up to 5 carbon the PEG is selected from the group consisting of PEG 200, atoms in their carbon chain skeleton, Such as ethanol, pro PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG panol, isopropanol, butanol, iso-butanol, t-butanol and pen 6000 and PEG 8000. The foamable carrier according to the tanol are considered less desirable solvents or co-solvents due present disclosure can contain a single PEG or a mixture of to their skin-irritating effect. Thus, according to some two or more PEGs. PEGs having molecular weight of more embodiments, the composition is Substantially alcohol-free that about 1000 possess gelling properties; i.e., they increase i.e., free of short chain alcohols. In other embodiments, the the Viscosity of a composition. Therefore, by combining composition comprises less than about 5% final concentra PEGs with different molecular weights/melting points, one tion of lower alcohols, preferably less than 2%, more prefer can attain varying levels of flowability as desirable for the ably less than 1%. treatment of a given target site. The concentration of the PEG should be in a level that results in viscosity, prior to filling of Skin Penetration Enhancer the composition into aerosol canisters, of less than 12,000 CPs, and more preferably, less than 10,000 CPs. 0297. A “skin penetration enhancer, also termed herein “penetration enhancer is an organic solvent, typically Secondary Solvent soluble in both water and oil. Examples of penetration enhancer include polyols, such as glycerol (glycerin), propy 0289 Optionally, a secondary solvent is added to the lene glycol, hexylene glycol, diethylene glycol, propylene foamable composition of the present disclosure. The second glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen ary solvent is selected from a variety of organic solvents that ols, limonene, terpene-ol. 1-menthol, dioxolane, ethylene are typically miscible on both water and oil. Examples of glycol, hexylene glycol, other glycols, Sulfoxides, such as solvent that can be contained in the foamable carrier of the dimethylsulfoxide (DMSO), dimethylformanide, methyl present disclosure include dimethyl isosorbide, tetrahydro dodecyl sulfoxide, dimethylacetamide, dimethylisosorbide, furfuryl alcohol polyethyleneglycol ether (glycofurol), monooleate of ethoxylated glycerides (with 8 to 10 ethylene DMSO, pyrrolidones, (such as N-Methyl-2-pyrrolidone and oxide units), aZone (1-dodecylazacycloheptan-2-one), 2-(n- 1-Methyl-2-pyrrolidinone), ethyl proxitol, dimethylaceta nonyl)-1,3-dioxolane, esters, such as isopropyl myristate/ mide (DMAc), PEG-type surfactants and alpha hydroxy palmitate, ethyl acetate, butyl acetate, methyl proprionate, acids, Such as lactic acid and glycolic acid. capric/caprylic triglycerides, octylmyristate, dodecyl myristate, myristyl alcohol, lauryl alcohol, lauric acid, lauryl Solubilization and Penetration Enhancement lactate ketones; amides, such as acetamide oleates such as 0290. In many cases, polyols, PEGs and solvents possess a triolein; various alkanoic acids such as caprylic acid; lactam high solubilizing power and thus, they can enable increased compounds, such as aZone; alkanols, such as dialkylamino concentrations of a pharmaceutical active agent. Polyols, acetates, and admixtures thereof. PEGs and solvents are also known for their skin penetration 0298. According to one or more embodiments, the pen enhancement properties. These properties enable high drug etration enhancer is a polyethylene glycol (PEG) or PEG bioavailability in the target area of treatment, resulting in an derivative that is liquid at ambient temperature. enhanced therapeutic effect. Occasionally, combinations of a 0299 Suitable skin penetration enhancers include but are polyol, PEGs and a secondary solvent, exhibit an increased not limited to acetone, acyl lactylates, acyl peptides, acylsar US 2010/031 0476 A1 Dec. 9, 2010

cosinates, alkanolamine salts of fatty acids, alkyl benzene is present in a solid State. In one or more embodiments, the Sulphonates, alkyl ether Sulphates, alkyl Sulphates, anionic concentration of the at least one potent solvent is more than Surface-active agents, benzyl benzoate, benzyl salicylate, about 40% of the at least one solvent of the composition of the butan-1,4-diol, butylbenzoate, butyl laurate, butyl myristate, present disclosure; or even more than about 60%. butyl Stearate, cationic Surface-active agents, citric acid, 0302) Non-limiting examples of pairs of active agent and cocoamidopropylbetaine, decyl methyl Sulfoxide, decyl ole potent solvent include: Betamethasone Valerate: Practically ate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, insoluble in mineral oil (<0.01%); soluble more than 1% in dibutyl sebacate, dibutyl suberate, dibutyl succinate, dicapryl glycofurol; Hydrocortisone butyrate: Practically insoluble in adipate, didecyl phthalate, diethylene glycol, diethyl seba mineral oil (<0.01%); soluble more than 1% in glycofurol; cate, diethyl-m-toluamide, di(2-hydroxypropyl)ether, diiso Metronidazole: Practically insoluble in mineral oil (<0.01%); propyl adipate, diisopropyl sebacate, N,N-dimethyl aceta soluble more than 1% in dimethyl isosrbide; Ketoconazole: mide, dimethyl azelate, N,N-dimethyl formamide, 1.5- Practically insoluble in mineral oil (<0.01%); soluble more dimethyl-2-pyrrolidone, dimethyl sebacate, dimethyl than 1% in glycofurol, propylene glycol and dimethyl isosr Sulphoxide, dioctyladipate, dioctyl azelate, dioctyl sebacate, bide; Mupirocin: Practically insoluble in mineral oil (<0. 1.4 dioxane, 1-dodecylazacyloheptan-2-one, dodecyl dim 0.1%); soluble more than 1% in glycofurol, hexylene glycol, ethylamine oxides, ethyl caprate, ethyl caproate, ethyl capry dimethyl isosorbide, propylene glycol and polyethylene gly late, 2-ethyl-hexyl pelargonate, ethyl-2-hydroxypropanoate, col 400 (PEG 400); Meloxicam, a nonsteroidal anti-inflam ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl matory agent: Practically insoluble in mineral oil (<0.001%); salicylate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydrox soluble in propylene glycol: 0.3 mg/mL, and in PEG 400: 3.7 ypropanoic acid, 2-hydroxypropionic acid, isethionates, iso mg/mL, and Progesterone: Practically insoluble in mineral propyl isostearate, isopropyl palmitate, guar hydroxypropyl oil (<0.001%); soluble in PEG 400: 15.3 mg/mL. trimonium chloride, hexan-2,5-diol, khellin, lamepons, 0303 A non-limiting exemplary list of solvents that can be lauryl alcohol, maypons, metal salts of fatty acids, methyl considered as potent solvents includes polyethylene glycol, nicotinate, 2-methyl propan-2-ol. 1-methyl-2-pyrrolidone, propylene glycol, hexylene glycol, butaneediols and isomers 5-methyl-2-pyrrolidone, methyl taurides, miranol, nonionic thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl Surface-active agents, octyl alcohol, octylphenoxy poly caprylate, diisopropyl adipate, dimethylacetamide, N-meth ethoxyethanol, oleic ethanolamide, pleyl alcohol, pentan-2, ylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyr 4-diol, phenoxyethanol, phosphatidyl choline, phosphine rolidone, isosorbide derivatives, such as dimethyl isosorbide, oxides, polyalkoxylated ether glycollates, poly(diallylpiperi glycofurol and ethoxydiglycol (transcutol) and laurocapram. dinium chloride), poly(dipropyldiallylammonium chloride), 0304. The use of a potent solvent in a foam composition polyglycerol esters, polyoxyethylene lauryl ether, polyoxy: provides an improved method of delivering poorly soluble polyoxyethylene Stearate, polyoxypropylene 15 Stearyl ether, therapeutic agents to a target area. It is known that low drug poly(vinyl pyridinium chloride), propan-1-ol, propan-2-ol. solubility results in poor bioavailability, leading to decreased propylene glycol dipelargonate, pyroglutamic acids, 2-pyr effectiveness of treatment. Foam compositions of the present rolidone, pyruvic acids, Quaternium 5. Quaternium 18, disclosure, for which the solvent includes a potent solvent, Quaternium 19, Quaternium 23, Quaternium 31, Quaternium increase the levels of the active agent in solution and thus, 40, Quaternium 57, quartenary amine salts, quaternised poly provide high delivery and improved therapy. (dimethylaminoethylmethacryl-ate), quaternised poly (vinyl 0305 Potent solvents, as defined herein, are usually liquid. alcohol), Sapamin hydrochloride, sodium cocaminopropi Formulations comprising potent solvents and active agents onate, Sodium dioctyl Sulphonsuccinate, Sodium laurate, are generally disadvantageous as therapeutics, since their Sodium lauryl ether Sulphate, Sodium lauryl Sulphate, Sugar usage involves unwanted dripping and inconvenient method esters, Sulphosuccinate, tetrahydrofuran, tetrahydrofurfural of application; resulting in inadequate dosing. Surprisingly, alcohol, transcutol, triethanolamine dodecylbenzene Sulpho the foams of the present disclosure, which are drip-free, pro nate, triethanolamine oleate, urea, water and derivatives, vide a Superior vehicle for Such active agents, enabling con esters, salts and mixtures thereof. Venient usage and accurate effective dosing. 0306 In one or more embodiments of the present disclo Potent Solvent Sure the present disclosure the foamable pharmaceutical com 0300. In one or more embodiments of the present disclo position may additionally include a mixture of two or more of Sure, the foamable composition includes a potent solvent, in the solvents selected from the group of hydrophobic solvents, addition to or in place of one of the hydrophobic solvents, silicone oils, emollients, polar solvents and potent solvents in polar solvents or emollients of the composition. A potent an appropriate proportion as would be appreciated to a person solvent is a solvent other than mineral oil that solubilizes a skilled in the art. specific active agent Substantially better than a hydrocarbon 0307. In one or more embodiments of the present disclo Solvent such as mineral oil or petrolatum. For example, a sure, the PPG alkyl ether may act as a potent solvent potent solvent solubilizes the active agent 5 fold better than a hydrocarbon solvent; or even solubilizes the active agent Modulating Agent 10-fold better than a hydrocarbon solvent. 0308 The term modulating agent is used to describe an 0301 In one or more embodiments of the present disclo agent which can improve the stability of or stabilize a carrier Sure, the composition includes at least one active agent in a or a foamable composition and or an active agent by modu therapeutically effective concentration; and at least one lating the effect of a substance or residue present in the carrier potent solvent in a sufficient amount to Substantially solubi or composition. The Substance or residue may for example be lize the at least one active agent in the composition. The term acidic or basic and potentially alteran artificial pH in a water “substantially soluble” means that at least 95% of the active less or Substantially non aqueous environment or it may be agent has been solubilized, i.e., 5% or less of the active agent one or more metal ions which may act as a potential catalyst

US 2010/031 0476 A1 Dec. 9, 2010

0325 For instance it is known that Polyphenols through be more stable in a waterless composition. For example, the chelation of transition-metal ions, particularly those of ascorbic acid in aqueous solution is known to be more stable iron and copper inhibit free radical formation and the propa at an acidic pH of about 5.4. It is therefore desirable to add a gation of free radical reactions (Brown et al. in Biochem. J. combination of modulating agents in a waterless composition 330, 1173 1178 (1998)). Citric acid, amino acids, and thyl that will generate an artificial pH approximately of the order enediaminetetraacetic acid also form chelates with metallic of or equivalent to that at which ascorbic acid is more stable ions such as copper and iron, thus avoiding their catalytic in a waterless medium. In order to do so it will be appreciated action on the oxidation of lipids. Most of these chelating a man of the art that that some adjustment will have to be agents exhibit little or no antioxidant activity when used made as ascorbic acid is itself a strong acid and displays the alone, and therefore they are considered as synergistic agents characteristics of a modulating agent. Similarly chelating of other antioxidants. Thus, they increase, to a great extent, the action of primary antioxidants. agents may be usefully used in combination with another 0326 In one or more embodiments of the present disclo modulating agent such as an acid, a base or a buffer system or Sure the chelating agent is selected from the group consisting with various combinations of modulating agents. of acetyl trihexyl citrate, aminotrimethylene phosphonic 0331. The modulating agent to the foamable composition acid, beta-alanine diacetic acid, bismuth citrate, calcium of the present disclosure is further useful for adjusting the pH disodium edita, citric acid, cyclohexanediamine tetraacetic of the target area of application. Skin is the first line of defense acid, diammonium citrate, dibutyl oxalate, diethyl oxalate, against all elements, such as microorganisms, wind, and pol disobutyl oxalate, diisopropyl oxalate, dilithium oxalate, lutants, and it's the acid mantle, a fine film with a slightly dimethyl oxalate, dipotassium edita, dipotassium oxalate, acidic pH on the surface of the skin that provides protection dipropyl oxalate, disodium edita, disodium edita-copper, diso for the skin. It plays a very important role as an integral part dium pyrophosphate, edita, etidronic acid, hedta, methyl of the barrier function of the stratum corneum. Recent studies cyclodextrin, oxalic acid, pentapotassium, triphosphate, pen have demonstrated that increased enzyme activity of phos tasodium aminotrimethylene phosphonate, pentasodium pholipase A2 is related to the formation of the acid mantle in pentetate, pentasodium triphosphate, pentetic acid, phytic the stratum corneum. This combination makes the skin less acid, potassium citrate, Sodium citrate, sodium dihydroxyeth permeable to water and other polar compounds. Normal skin ylglycinate, Sodium gluceptate, sodium gluconate, sodium surface pH is between 4 and 6.5 in healthy people, though it hexametaphosphate, Sodium metaphosphate, sodium meta varies among the different areas of the skin. Newborn infants silicate, sodium oxalate, sodium trimetaphosphate, tea-edita, do have a higher skin Surface pH compared to adults, but this tetrahydroxypropyl ethylenediamine, tetrapotassium etidr normalizes within three days. Therefore, it is important to onate, tetrapotassium pyrophosphate, tetrasodium edita, tetra maintain skin Surface pH in order to prevent Susceptibility to Sodium etidronate, tetrasodium pyrophosphate, tripotassium bacterial skin infections or skin damage and disease. Thus, edita, trisodium edita, trisodium hedta, trisodium inta, triso adding a modulating agent, which contributes to the stabili dium phosphate, malic acid, fumaric acid, maltol, Succimer, Zation of skin pH at the desirable level, is advantageous. penicillamine, dimercaprol, and desferrioxamine mesilate. 0332. In the same fashion, adding an acidic modulating 0327 Other authorized chelating agents are listed pursu agent to a foamable composition, which is intended for vagi ant to annex 1, paragraph E.3.1 of regulation (EC) No 2003 nal application is advantageous, since the best protection (See Directive 67/548/EEC OJ 196, 16.8 1967, p1) and are against vaginal infection is attained in pH lower than 4. also incorporated herein by reference. 0333 While the organic modulating agent can serve to 0328. In one or more preferred embodiments of the stabilize an active agent in the foam composition, it often present disclosure the chelating agent is selected from the provides additional therapeutic properties to the composition. group consisting of ethylenediaminetetraacetic acid The following table exemplifies, in a non-limiting fashion, (“EDTA) and salts thereof such as disodium EDTA, tetraso the therapeutic benefits expected from an organic modulating dium EDTA and callsium disodium EDTA; diethylenetri agent. It is to be understood that this table provides a non aminepentaacetic acid (“DTPA) and salts thereof; hydroxy exhaustive list of modulating agents that possess therapeutic ethlethylenediaminetriacetic acid (“HEDTA) and salts effects, however, many other compounds listed in the present thereof and nitrilotriacetic acid (“NTA); more preferably specification also possess therapeutic benefits. EDTA, HEDTA and their salts; most preferably EDTA and its salts. 0329. In one or more embodiments of the present disclo Exemplary therapeutic Sure a preferred nonlimiting example of the chelating agentis Class Examples properties EDTA. Typically, the chelating and sequestering agent is Alpha hydroxy acids Lactic acid Humectant present in the composition at a level of up to about 5.0%, Glycolic acid Keratinocyte growth preferably 1.0 percent, by weight, of the composition. modifier 0330 Combinations of Modulating Agents may be a use Anti-psoriasis Anti acne ful aspect of the present disclosure. For example, as will be Beta hydroxyl acid Salicylic acid Keratolytic appreciated by a man of the art combinations of a strong acid Antiinflammatory and a weak base; a weak acid and a strong base: a weak acid Short chain carboxylic Propionic acid Antiinfective and a strong acid; a weak base and a strong base; a weak base acid Butyric acid Fatty acids Nonanoic acid Hair growth stimulant and a second weak base; and a weak acid and a second weak Behemic acid Antiinflammatory acid; may prove more effective in protecting or stabilizing an Antiinfective active agent in the waterless solvents of the present disclosure Humectant thanabase or acid on its own. It will be understood that each Skin protection of the active agents may have an artificial pH at which it can US 2010/031 0476 A1 Dec. 9, 2010 22

lamine, amino-guanidine), Sulfhydryl compounds (e.g., glu -continued tathione), dihydroxy fumaric acid and its salts, lycine pidol ate, arginine pilolate, nordihydroguaiaretic acid, Exemplary therapeutic bioflavonoids, curcumin, lysine, methionine, proline, Super Class Examples properties oxide dismutase, silymarin, tea extracts, grape skin/seed Unsaturated fatty acids Omega-3 fatty acids Radical scavenger extracts, melanin, and rosemary extracts may be used. Omega-6 fatty acids Anti-oxidant Aromatic acids Benzoic acid Antiinflammatory 0338. In one or more embodiments the modulating agent Phthalic acid Anti-acne is a flavonoid. Nicotinic acid Anti-pigmentation Antiinfective 0339 Flavonoids (or bioflavonoids) are a large group of insect repellant polyphenolic antioxidant compounds, which often occur as Dicarboxylic acids Malonic acid, Succinic Antiinflammatory glycosides and are ubiquitously present in foods of plant acid, glutaric acid, Keratolytic origin. Some flavonoids (e.g. quercetin, rutin) are available as adipic acid, pimelic Anti-acne dietary supplements. Flavonoids can be further subdivided acid, Suberic acid, Anti-rosacea aZelaic acid, sebacic Anti-pigmentation into: acid 0340 flavonols (e.g. kaempferol, quercetin and myrice Amino acids Keratinocyte growth modifier tin) Hair growth stimulant 0341 flavones (e.g. apigenin and luteolin) Sebum control 0342 flavonones (e.g. hesperetin, naringenin, eriodic Retinoids Retinoic acid Antiinflammatory Isotretinoin Keratolytic tyol) Anti-acne 0343 flavan-3-ols (e.g. (+)-catechin, (+)-gallocatechin, Anti-rosacea (-)-epicatechin, (-)-epigallocatechin) Anti-pigmentation Nitrogen containing Urea Humectant 0344 anthocyanins (e.g. cyanidin, delphinidin, malvi Keratolytic din, pelargonidin, peonidin, petunidin) Anti-psiriasis 0345 proanthocyanidins. 0346 More than 4000 flavonoids have been identified, and 0334. In an embodiment where the modulating agent is a many have been studied. Most are colorless but some are buffer or pH adjuster Surprisingly such modulating agents responsible for the bright colors of many fruit and vegetables. have been found to be incompatible with minocycline Flavonoids are distinguished from the carotenoids. although they may in certain embodiments be compatible 0347 Flavonoids appear to with doxycycline. In an embodiment the modulating agent is 0348 act as Scavengers of free radicals, including other than a buffer or pH modifier. Superoxide anions, singlet oxygen, and lipid peroxyl Anti-Oxidants/Radical Scavengers radicals (they have antioxidant properties); 0349 sequester metal ions; 0335. In one or more embodiments, the modulating agent 0350 inhibit in vitro oxidation of LDL cholesterol: may also be a preservative or an antioxidant or an ionization agent. Any preservative, antioxidant or ionization agents Suit 0351 inhibit cyclo-oxygenase, leading to lower platelet able for pharmaceutical or cosmetic application may be used. aggregation, decreased thrombotic tendency and Non limiting examples of antioxidants are tocopherol Succi reduced anti-inflammatory activity; nate, propyl galate, butylated hydroxy toluene and butyl 0352 inhibit histamine release: hydroxyanisol. Ionization agents may be positive or may be 0353 improve capillary function by reducing fragility negative depending on the environment and the active agent of capillary walls and thus preventing abnormal leakage; or composition that is to be protected. Ionization agents may and for example act to protect or reduce sensitivity of active 0354 inhibit various stages of tumor development (ani agents. Non limiting examples of positive ionization agents mal studies only). are benzyl conium chloride, and cetyl pyridium chloride. Non 0355 The activities of flavonoids are dependent on their limiting examples of negative ionization agents are sodium chemical structure. Estimates of dietary flavonoid intake vary lauryl Sulphate, sodium lauryl lactylate and phospholipids. from 10 to 100 mg daily, but may be several hundreds of 0336 A safe and effective amount of an anti-oxidant/radi milligrams a day. Dietary Supplements of quercetin and rutin cal Scavenger may be added to the compositions of the Subject provide around 500 mg in a single dose. disclosure, preferably from about 0.1% to about 10%, more 0356 Flavonoids may have a potential role in the preven preferably from about 1% to about 5%, of the composition. tion of CVD, cancer and cataracts and possibly other dis 0337 Anti-oxidants/radical scavengers such as ascorbic eases, for anti-viral activity., and they may be useful in treat acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ing ulcers. include hemorrhoids, allergy, asthma, menopausal ascorbic acid derivatives (e.g., magnesium ascorbyl phos symptoms and the prevention of habitual abortion. phate, sodium ascorbyl phosphate, ascorbyl Sorbate), toco pherol (vitamin E), tocopherol Sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxybenzoic acids Quercetin and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2- 0357. As a dietary supplement, quercetin is promoted for carboxylic acid (commercially available under the tradename prevention and treatment of atherosclerosis and hyperlipi Trolox. Sup.R), gallic acid and its alkyl esters, especially pro daemia, diabetes, cataracts, hay fever, peptic ulcer, inflam pyl gallate, uric acid and its salts and alkyl esters, Sorbic acid mation, prevention of cancer and for treating prostatitis. A and its salts, lipoic acid, amines (e.g., N,N-diethylhydroxy preliminary, double-blind, placebo-controlled trial in chronic US 2010/031 0476 A1 Dec. 9, 2010 non-bacterial prostatitis showed that quercetin reduced pain the waterless compositions of the present disclosure may be and improved quality of life, but had no effect on voiding selected as will be appreciated by a person skilled in the art. dysfunction. Moisturizers Rutin 0364. A moisturizer, is a substance that helps retain mois ture or add back moisture to the skin. Examples are allantoin, 0358 As a dietary supplement, rutin is used to reduce petrolatum, urea, lactic acid, sodium PCV, glycerin, shea capillary permeability and treat symptoms of varicose veins. butter, caprylic/capric/stearic triglyceride, candelilla wax, In combination with bromelain and trypsin, rutin is used to propylene glycol, lanolin, hydrogenated oils, squalene, treat osteoarthritis. sodium hyaluronate and lysine PCA. Glycerine and sodium 0359 A non limiting list of flavonoid compounds is: ben pCA work in combination. Other examples may be found in Zquercin, dioSmin, ethoxazorutoside, flavodate, sodium hes the Handbook of Pharmaceutical Additives published by peridin, leucocianido, monoxerutin, oxerutin, quercetin, Gower. rutoside, roSmarinic acid. The above information was noted 0365 Pharmaceutical compositions of the present disclo from Dietary Supplements, Electronic Version, Pharmaceu Sure may in one or more embodiments usefully comprise in tical Press 2007. addition a humectant or a moisturizer or combinations 0360. In an embodiment a single flavonoid is provided and thereof. in a further embodiment a combination of two or more fla vonoid are provided. In certain embodiments the flavonoids Additional Components act synergistically. In an embodiment water soluble fla 0366. In an embodiment of the present disclosure, a com vonoids are combined with water insoluble flavonoids. It is position of the present disclosure includes one or more addi known for example that whole polyphenolic extracts have tional components. Such additional components include but greater antioxidant effect than their known individual com are not limited to anti perspirants, anti-static agents, buffering ponents. In an embodiment flavonoids are used in combina agents, bulking agents, chelating agents, cleansers, colorants, tion with other phenolics. In an embodiment one or more conditioners, deodorants, diluents, dyes, emollients, fra flavonoids are provided in combination with one or more grances, hair conditioners, humectants, pearlescent aids, per vitamins. In an embodiment flavonoids are provided that are fuming agents, permeation enhancers, pH-adjusting agents, more reactive than the vitamins. In an embodiment the fla preservatives, protectants, skin penetration enhancers, Soft vonoids act as a conservational agent. eners, solubilizers, Sunscreens, Sun blocking agents, Sunless tanning agents, viscosity modifiers and vitamins. AS is known MicroSponges to one skilled in the art, in some instances a specific additional component may have more than one activity, function or 0361 The MicroSponges are rigid, porous and spongelike effect. round microscopic particles of cross-linked polymer beads 0367. In an embodiment of the present disclosure, the (e.g., polystyrene or copolymers thereof), each defining a additional component is a pH adjusting agent or a buffering substantially noncollapsible pore network. The Micro agent. Suitable buffering agents include but are not limited to sponges can be loaded with an active ingredient and can acetic acid, adipic acid, calcium hydroxide, citric acid, gly provide a controlled time release of the active ingredient to cine, hydrochloric acid, lactic acid, magnesium alumi skin or to a mucosal membrane upon application of the for nometasilicates, phosphoric acid, sodium carbonate, sodium mulation. The slow release is intended to reduce irritation by citrate, Sodium hydroxide, Sorbic acid, Succinic acid, tartaric the active. Microsponge R. delivery technology was devel acid, and derivatives, salts and mixtures thereof. oped by Advanced Polymer Systems. In one or more embodi 0368. In an embodiment of the present disclosure, the ments the composition comprises one or more active agents additional component is a humectant. loaded into Microponges with a waterless carrier described 0369. In an embodiment no preservative is added since the herein which may comprise a modulating agent. formulation is a waterless oil base formulation having an Aw (WaterActivity) value of less than 0.5 which is below the level of microbial proliferation. In certain limited an embodiments, Humectant the additional component is an oil soluble preservative. Suit 0362. A humectant, is a substance that helps retain mois able preservatives include but are not limited to C12 to C15 ture and also prevents rapid evaporation. Non limiting alkylbenzoates, alkyl p-hydroxybenzoates, aloe Vera extract, ascorbic acid, benzalkonium chloride, benzoic acid, benzoic examples of Suitable heumectants are propylene glycol, pro acid esters of C9 to C15 alcohols, butylated hydroxytoluene, pylene glycol derivatives, and glycerin. Further humectants castor oil, cetyl alcohols, chlorocresol, citric acid, cocoa but include but are not limited to guanidine, urea, glycolic acid, ter, coconut oil, diazolidinyl urea, diisopropyl adipate, dim glycolate salts, ammonium glycolate, quaternary alkyl ethyl polysiloxane, DMDM hydantoin, ethanol, fatty acids, ammonium glycolate, lactic acid, lactate salts, ammonium fatty alcohols, hexadecyl alcohol, hydroxybenzoate esters, lactate, quaternary alkyl ammonium lactate, aloe Vera, aloe iodopropynyl butylcarbamate, isononyl iso-nonanoate, Vera gel, allantoin, urazole, alkoxylated glucose, hyaluronic jojoba oil, lanolin oil, methylparaben, mineral oil, oleic acid, acid, lactamide monoethanolamine, acetamide monoethano olive oil, polyoxypropylene butyl ether, polyoxypropylene lamine and derivatives, esters, salts and mixtures thereof. cetyl ether, potassium Sorbate, silicone oils, sodium propi 0363. Other examples of humectants and moisturizers onate, sodium benzoate, sodium bisulfite, Sorbic acid, Stearic may be found in the Handbook of Pharmaceutical Additives fatty acid, vitamin E. vitamin Eacetate and derivatives, esters, published by Gower. Suitable ones for use with and soluble in salts and mixtures thereof. US 2010/031 0476 A1 Dec. 9, 2010 24

0370. In an embodiment of the present disclosure, the organism has a limiting AW, below which it will not grow, e.g., additional component is a skin penetration enhancer. for Streptococci, klebsiella spp., escherichia coli, clostridium perfingens, and pseudomonas spp. the w value is 0.95. Propellants Staphylococcus aureus is most resistant and can proliferate 0371 Examples of suitable propellants include volatile with an A as low as 0.86. hydrocarbons such as butane, propane, isobutane and fluoro 0379 The water activity of a product can be determined carbon gases, or mixtures thereof. from the relative humidity of the air surrounding the sample 0372. In an embodiment the propellant is 1681, which is a when the air and the sample are at equilibrium. Measurement mixture of propane, isobutene and butane. In another embodi is performed by placing a sample in an enclosed space where ment it is AP70, which is a mixture of propane, isobutene and this equilibrium can take place. Once this occurs, the water butane with a higher pressure. activity of the sample and the relative humidity of the air are 0373 The propellant makes up about 5-25 wt % of the equal. The measurement taken at equilibrium is called an foamable composition. In some circumstances the propellant equilibrium relative humidity or ERH. The relationship may be up to 35%. The propellants are used to generate and between the wateractivity and ERH is in accordance with the administer the foamable composition as a foam. The total following formula: composition including propellant, foamable compositions A=ERH/100 and optional ingredients is referred to as the foamable com 0380 Various types of wateractivity instruments are com position. mercially available. One exemplary instrument uses chilled 0374. Alcohol and organic solvents render foams inflam mirror dewpoint technology while other instruments measure mable. It has been surprisingly discovered that fluorohydro relative humidity with sensors that change electrical resis carbon propellants, other than chloro-fluoro carbons tance or capacitance. (CMCs), which are non-oZone-depleting propellants, are par 0381 Polyols, PEGs and other solvents have a great affin ticularly useful in the production of a non-flammable foam ity for water, and as such, they exhibit hygroscopic properties. able composition. A test according to European Standard The concentration of the polyol, the PEG and/or other sol prEN 14851, titled “Aerosol containers-Aerosol foam flam vents determines the Aw of the carrier. In one or more mability test” revealed that compositions containing an embodiments, the polyols, the PEG and/or the secondary organic carrier that contains a hydrophobic organic carrier Solvent is contained in the composition of the present disclo and/or a solvent, which are detected as inflammable when a Sure at a sufficient concentration to provide an A value of the hydrocarbon propellant is used, become non-flammable, hygroscopic carrier of less than 0.9. In other embodiments, while the propellant is an HFC propellant. the concentration of the polyol, the PEG and/or secondary 0375 Such propellants include, but are not limited to, solvent in the composition is selected to provide an A value hydrofluorocarbon (HFC) propellants, which contain no selected from the ranges of (1) about 0.8 and about 0.9; (2) chlorine atoms, and as such, fall completely outside concerns about 0.7 and about 0.8; and (3) less than about 0.7. about stratospheric ozone destruction by chlorofluorocarbons 0382. As such, a composition containing a polyol, a PEG or other chlorinated hydrocarbons. Exemplary non-flam with or without a secondary solvent can be used as topical mable propellants according to this aspect of the disclosure treatment of Superficial infectious conditions. include propellants made by DuPont under the registered 0383. The advantage of providing a hygroscopic compo trademark Dymel, such as 1,1,1,2 tetrafluorethane (Dymel sition in a pressurized packaging presentation is readily per 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227) 1.1, ceived. The usage of all other presentations, such as Solutions, difluoroethane (Dymel 152) and 1,1,1,3,3,3 hexafluoropro creams, lotions, ointments and the like involves repeated pane HFCs possess OZone Depletion Potential of 0.00 and opening of the package closure, resulting in absorption of thus, they are allowed for use as propellant in aerosol prod water from the Surrounding environment and a Subsequent uctS. elevation of the A (thus lowering the hygroscopicity of the 0376 Notably, the stability of foamable emulsions includ product, and therefore decreasing its anti-infective potential. ing HFC as the propellant can be improved in comparison By contrast, a pressurized packaging does not allow for any with the same composition made with a hydrocarbon propel humidity to be absorbed by the preparation, and therefore, the lant. hygroscopic character of the composition cannot be dam 0377. In one or more embodiments foamable composi aged. tions comprise a combination of a HFC and a hydrocarbon 0384. In one or more embodiments, the hygroscopic com propellant Such as n-butane or mixtures of hydrocarbon pro position of the present disclosure further contains an anti pellants such as propane, isobutane and butane. infective agent, selected from the group of an antibiotic agent, an antibacterial agent, an antifungal agent, an agent that con Hygroscopic Property of the Composition trols yeast, an antiviral agent and an antiparasitic agent. Com 0378. A hydroscopic substance is a substance that absorbs bining the anti-infective effect of a hygroscopic composition, water readily from its surroundings. Microorganisms require which acts through a dehydration mechanism, together with water to grow and reproduce, and Such water requirements are an additional anti-infective agent, that acts through alternate best defined in terms of water activity of the substrate. The mechanisms, results in a synergistic effect and consequently wateractivity of a solution is expressed as AP/Po, where P higher Success rate of the treatment. is the water vapor pressure of the solution and Po is the vapor pressure of pure water at the same temperature. Addition of a Composition and Foam Physical Characteristics and Advan hygroscopic Substance to an aqueous solution in which a tages microorganism is growing will have the effect of lowering the 0385) A pharmaceutical or cosmetic composition manu Aw, with a consequent effect upon cell growth. Every micro factured using the foamable carrier of the present disclosure is US 2010/031 0476 A1 Dec. 9, 2010 very easy to use. When applied onto the body surface of 0399. Foam texture should vary from a very fine creamy mammals, i.e., humans or animals, it is in a foam state, allow foam to a fine bubble structure. ing free application without spillage. Upon further applica 0400 Foam has to have specific gravity in the range of tion of a mechanical force, e.g., by rubbing the composition about 0.02 gr/mL to about 0.5 gr/mL, more preferably onto the body surface, it freely spreads on the surface and is between about 0.04 gr/mL and about 0.2 gr/mL rapidly absorbed. 04.01. In terms of spreadability and absorption an accept 0386 The foamable composition of the present disclosure able foam is one, that does not readily collapse upon dispens is stable, having an acceptable shelf-life of at least one year, or ing on the skin; spreads easily on a skin Surface; at least preferably, at least two years at ambient temperature, as partially absorbed following rubbing onto the skin, and more revealed in accelerated Stability tests. Organic carriers and preferably, substantially absorbed following rubbing on the propellants tend to impair the stability of emulsions and to skin. interfere with the formation of stable foam upon release from 0402. In terms of tactile properties an acceptable foam is a pressurized container. It has been observed, however, that one, that: creates a pleasant feeling after application; leaves the foamable compositions according to the present disclo minimal oily residue; and leaves minimal shiny residual look. Sure are Surprisingly stable. Following accelerated Stability studies, they demonstrate desirable texture; they form fine Foam Collapse bubble structures that do not break immediately upon contact with a Surface, spread easily on the treated area and absorb 0403. A further aspect of the foam is breakability. Ther quickly. mally sensitive foams immediately collapse upon exposure to skin temperature and, therefore, cannot be applied on the 0387. The composition should also be free flowing, to hand and afterwards delivered to the afflicted area. allow it to flow through the aperture of the container, e.g., and 04.04 The foam of the present disclosure has several aerosol container, and create an acceptable foam. notable advantages, when compared with hydroalcoholic foam compositions, such as Quantitative and Qualitative 04.05 (1) Breakability. The foam of the present disclosure 0388 Foam Quality is thermally stable and breakable under sheer force but is 0389 Foam quality can be graded as follows: not "quick breaking which allows comfortable application 0390 Grade E (excellent): very rich and creamy inappear and well directed administration to the target area; ance, does not show any bubble structure or shows a very fine 0406 (2) Skin drying and skin barrier function. Short (small) bubble structure, does not rapidly become dull; upon chain alcohols are known to dry the skin and impair the spreading on the skin, the foam retains the creaminess prop integrity of the skin barrier. By contrast, including a film erty and does not appear watery. forming agent in the composition of the present disclosure 0391 Grade G (good): rich and creamy in appearance, foes not cause unwanted skin barrier damage. very small bubble size, “dulls' more rapidly than an excellent (0407 (3) Irritability. Due to the lack of lower alcohols foam, retains creaminess upon spreading on the skin, and (C1-C5) and improvement in skin barrier function, skin does not become watery. irritability is eliminated. 0392 Grade FG (fairly good): a moderate amount of 0408. Another property of the foam is specific gravity, as creaminess noticeable, bubble structure is noticeable; upon measured upon release from the aerosol can. Typically, foams spreading on the skin the product dulls rapidly and becomes have specific gravity of less than 0.12 g/mL, or less than 0.10 Somewhat lower in apparent viscosity. g/mL, or less than 0.08 g/mL, depending on their composition 0393 Grade F (fair): very little creaminess noticeable, and on the propellant concentration. larger bubble structure than a “fairly good' foam, upon spreading on the skin it becomes thin in appearance and Pharmaceutical Composition watery. 04.09. The foamable composition of the present disclosure 0394 Grade P (poor): no creaminess noticeable, large (also referred to herein as the foamable pharmaceutical com bubble structure, and when spread on the skin it becomes very position) is an ideal vehicle for active pharmaceutical ingre thin and watery in appearance. dients and/or active cosmetic ingredients. In the context of the 0395 Grade VP (very poor): dry foam, large very dull present disclosure, active pharmaceutical ingredients and bubbles, difficult to spread on the skin. active cosmetic ingredients are collectively termed “active 0396 Topically administrable foams are typically of qual agent' or “active agents'. The silicone and oil waterless for ity grade E or G, when released from the aerosol container. mulations optionally coupled with the use of modulating Smaller bubbles are indicative of more stable foam, which agents can uniquely be adapted to protect and preserve active does not collapse spontaneously immediately upon discharge agents when stored in compatible sealed canisters with pro from the container. The finer foam structure looks and feels pellant A foamable composition, comprising an active agent Smoother, thus increasing its usability and appeal. has the following advantages: 0410) 1. The foamable composition provides a pre Foam Physical Characteristics ferred solvent for active agents, particularly for poorly Soluble or water-insoluble agents. 0397. In terms of foam consistency and texture an accept 0411 2. The provision of an essentially single phase able foam is one, that exhibits the following characteristics: foamable composition facilitates a co-solvent effect, 0398. Upon release from an aerosol can, creates a foam resulting increased concentrations of soluble active mass, which is Sustained on a surface for at least one minute, agent in the dosage form, thus facilitating enhanced skin more preferably at least two minutes, and yet more preferably penetration of the active agent. In many cases, increased for at least 5 minutes. penetration is positively correlated with improved clini US 2010/031 0476 A1 Dec. 9, 2010 26

cal outcome. In certain case, attaining an increased drug list of non limiting examples of oil soluble active agents penetration into the target site of action enables a include calcipotriol, calcitriol, ciclopiroX olamine, ben decrease of treatment frequency, for example, from Zocaine. Other examples are terbinofine, diclofenac, tacroli twice or three times daily to once daily. Oils with a mus and pimecrolimus and also oil soluble vitamins. Estra secondary solvent can act as skin penetration enhancers, diol, progesterone are non limiting examples of sparingly oil thus, increasing drug residence time in the target area soluble agents. and increasing clinical efficacy, as detailed above. 0420 Because the prefoam formulations can provide a 0412 Similarly, the inclusion of a polyol and/or a Substantially waterless, high oil content environment, par PEG and/or a polyol ether and in the foamable com ticular classes of active pharmaceutical ingredients (APIs) position facilitates a co-solvent effect, resulting will benefit from their inclusion in the composition. For increased concentrations of soluble active agent in the example, active agents that are water sensitive, Such as dosage form, thus facilitating enhanced skin penetra minocycline, doxycycline and other tetracycline drugs, vita tion of the active agent. In many cases, increased min D (e.g., calcipotriol and calcitriol), can have improved penetration is positively correlated with improved stability in the waterless composition. API's that are esters or clinical outcome. In certain case, attaining an amides are generally prone to hydrolysis by water and would increased drug penetration into the target site of benefit from a water free oil environment. API's that are action enables a decrease of treatment frequency, for sensitive to free radical attack or oxidation also would benefit example, from twice or three times daily to once daily. from a water free oil environment. Similarly, active agents 0413 3. Polyols, polyol ethers and PEGs; and combi that are sensitive to specific pH level (which prevails in the nations of a polyol and/or PEG with a secondary solvent presence of water) will also benefit. Exemplary APIs that are known as skin penetration enhancers, thus, increas would benefit from the silicone waterless compositions ing drug residence time in the target area and increasing according to one or more embodiments include Vitamin D clinical efficacy, as detailed above. analogs and derivatives that degrade at low pH and corticos 0414. 4. The fact that the composition contains no or teroids that degrade at high pH. Oil soluble drugs can also be little water, minimizes the probability of degradation of included in the compositions, such as corticosteroids, immu water-sensitive active agents. Furthermore, as exempli nomodulators, such as tacrolimus and pimecrolimus, oil fied herein, a foam containing a polyol, a polyol ether soluble vitamins, e.g., vitamin A and derivatives thereof, and/or PEG with no water at all can be formed in accor other retinoids, vitamin E. Certain APIs may possess more dance with the composition and process of the present than one of the above features, and thereby benefit even disclosure. Such compositions ensure high stability of further from the silicone waterless compositions. water sensitive active agents. 0421. Thus, in a preferred embodiment of the present dis 0415 5. Combining the anti-infective effect of a hygro closure, the composition includes at least one active agent. Scopic composition, which acts through a dehydration 0422 a. a therapeutically effective concentration of an mechanism, with an additional anti-infective agent, active agent; Selected from the group of an antibiotic agent, an anti 0423) b. 10% to 30% by weight of at least one unstable bacterial agent, an antifungal agent, an agent that con active agent-compatible (UAAC) excipient selected trols yeast, an antiviral agent and an antiparasitic agent, from the group consisting of (1) a polyol and (2) a polyol that acts through alternate mechanisms results in a syn ether; ergistic effect and consequently higher Success rate of 0424 c. 10% to 60% by weight of at least one unstable the treatment. active agent-compatible (UAAC) emollient and or 0416 6. The foamable polyol composition in contained hydrophobic solvent; in an impermeable pressurized packaging presentation 0425 d. A stabilizing agent selected from the group is impermeable and thus, the active agent is not exposed consisting of about 0.01% to about 25% by weight of at to environmental degradation factors, such as light and least one surface-active agent; and about 0% to about 5% oxidating agent during storage. by weight of at least one polymeric agent and mixtures 0417 Thus, in one or more embodiments, the foamable thereof; composition includes at least one therapeutic agent, in a 0426 e. about 0 to about 10% by weight of at least one therapeutically effective concentration. Therapeutic agents alcohol; and are described herein. In addition, compounds disclosed in 0427 f. a liquefied or compressed gas propellant at a International Patent Publication No. WO 2004/03284, which concentration of about 3% to about 25% by weight of the is incorporated by reference in its entirety are suitable for use total composition. in the pharmaceutical compositions described herein. 0418. In an embodiment the therapeutic agent is soluble in Antibiotics the foamable composition. In alternative embodiments the 0428. In the context of the present disclosure, an antibiotic therapeutic agent is partially soluble and in further embodi agent is a Substance, that has the capacity to inhibit the growth ments the therapeutic agent is insoluble in the formulation. of or to destroy bacteria and other microorganisms. Where the agent is insoluble or partially soluble it is provided 0429. In one or more embodiments, the antibiotic agent is as a homogenous Suspension. In certain embodiments the selected from the classes consisting beta-lactam antibiotics, homogeneous Suspension remains homogenous over a Sub aminoglycosides, ansa-type antibiotics, anthraquinones, stantial period of time Suitable for pharmaceutical use. In antibiotic azoles, antibiotic glycopeptides, macrollides, anti other embodiments the agent may cram or separate out but biotic nucleosides, antibiotic peptides, antibiotic polyenes, homogeneity is fully reversible on shaking. antibiotic polyethers, quinolones, antibiotic steroides, Sul 0419 Oil soluble active agents may be readily used in the fonamides, tetracycline, dicarboxylic acids, antibiotic metals oil/silicone surfactant compositions described herein. A short including antibiotic metalions, oxidizing agents, a periodate, US 2010/031 0476 A1 Dec. 9, 2010 27 a hypochlorite, a permanganate, Substances that release free to determine at the time of injury which wounds will be radicals and/or active oxygen, cationic antimicrobial agents, self-healing. Therefore, some experts believe that, by reduc quaternary ammonium compounds, biguanides, triguanides, ing the number of Superficial bacteria, topical anti-infectives bisbiguanides and analogs and polymers thereof, naturally are useful for preventing infection in minor skin injuries (e.g., occurring antibiotic compounds, including antibiotic plant cuts, scrapes, burns). oils and antibiotic plant extracts and any one of the following 0435 Tetracycline hydrochloride may be used topically in antibiotic compounds including non classified antibiotic the treatment of inflammatory acne Vulgaris. Tetracyclines compounds analogs, derivatives, salts, ions, complexes and are usually bacteriostatic in action, but may be bactericidal in mixtures thereof: high concentrations or against highly Susceptible organisms. 0436 Tetracyclines appear to inhibit protein synthesis in Tetracyclines susceptible organisms primarily by reversibly binding to 30S ribosomal subunits, thereby inhibiting binding of aminoacyl 0430. The tetracyclines (also referred to herein as “tetra transfer-RNA to those ribosomes. In addition, tetracyclines cycline antibiotics') are a group of antibacterials, originally appear to reversibly bind to 50S ribosomal subunits. There is derived from certain Streptomyces spp., having the same tet preliminary evidence that tetracyclines also alter cytoplasmic racyclic nucleus, naphthacene, and similar properties. They membranes of Susceptible organisms resulting in leakage of are usually bacteriostatic but act by interfering with protein nucleotides and other intracellular components from the cell. synthesis in Susceptible organisms. Tetracycline antibiotics At high concentrations, tetracyclines also inhibit mammalian are susceptible to degradation by oxidation. protein synthesis. 0431 Tetracyclines include, but are not limited to, dihy 0437. The exact mechanisms by which tetracyclines drosteffimycin, demethyltetracycline, aclacinomycin, reduce lesions of acne Vulgaris have not been fully elucidated; akrobomycin, baumycin, bromotetracycline, cetocyclin, however, the effect appears to be partly the result of the chlortetracycline, clomocycline, daunorubicin, demeclocy antibacterial activity of the drugs. Following topical applica cline, doxorubicin, doxorubicin hydrochloride, doxycycline, tion to the skin of a 0.22% solution of tetracycline hydrochlo lymecyclin, marcellomycin, meclocycline, meclocycline Sul ride in a vehicle containing n-decyl methyl sulfoxide (Topi fosalicylate, methacycline, minocycline, minocycline hydro cycline(R); no longer commercially available in the US), the chloride, musettamycin, oxytetracycline, rhodirubin, rollitet drug inhibits the growth of susceptible organisms (principally racycline, rubomycin, serirubicin, Steffimycin, tetracycline Propionibacterium acnes) on the Surface of the skin and and analogs, salts and derivatives thereof. reduces the concentration of free fatty acids in sebum. The 0432 Chlortetracycline, oxytetracycline, tetracycline, reduction infree fatty acids in sebum may be an indirect result demeclocycline are all natural products that have been iso of the inhibition of lipase-producing organisms which con lated from Streptomyces spp. The more recent tetracyclines, vert triglycerides into free fatty acids or may be a direct result namely methacycline, doxycycline, and minocycline, are of interference with lipase production in these organisms. semisynthetic derivatives. Methacycline, like demeclocy Free fatty acids are comedogenic and are believed to be a cline, has a longer half-life than tetracycline. Minocycline is possible cause of the inflammatory lesions (e.g., papules, active against Some tetracycline-resistant bacteria, including pustules, nodules, cysts) of acne. However, other mechanisms strains of Staphylococci. Both doxycycline and minocycline also appear to be involved because clinical improvement of are more lipid-soluble than the other tetracyclines and they acne Vulgaris with topical tetracyclines does not necessarily penetrate well into tissues. They are thus more suitable for correspond with a reduction in the bacterial flora of the skin or incorporating into oily or emollient containing formulations. a decrease in the free fatty acid content of sebum. (Martindale However, they have a place in the treatment of chlamydial Electronic Version 2007) infections, rickettsial infections such as typhus and the spot ted fevers, mycoplasmal infections such as atypical pneumo Doxycyline nia, pelvic inflammatory disease, Lyme disease, brucellosis, tularaemia, plague, cholera, periodontal disease, and acne. 0438. Doxycycline is a tetracycline antibiotic and also has The tetracyclines have also been useful in the treatment of anti-inflammatory and immunomodulatory effects. Doxycy penicillin-allergic patients suffering from Venereal diseases, cline is a semisynthetic tetracycline antibiotic derived from actinomycosis, bronchitis, and leptospirosis. Minocycline oxytetracycline. In addition to antimicrobial activity, the drug may sometimes be used in multidrug regimens for leprosy. has anti-inflammatory and immunomodulatory effects. It is Doxycycline may be used for the treatment and prophylaxis available as Doxycycline calcium, doxycycline hyclate and of malaria; it is also used in the management of anthrax. doxycycline monohydrate. Doxycycline hyclate and doxycy 0433. In an embodiment the active ingredient may be any cline monohydrate occur as yellow, crystalline powders. The one of the following nonlimiting examples chlortetracycline, hyclate is soluble in water and slightly soluble in alcohol; the demeclocycline, doxycycline, lymecycline, meclocycline, monohydrate is very slightly soluble in water and sparingly methacycline, minocycline, oxytetracycline, rollitetracycline, soluble in alcohol. Doxycycline calcium is formed in situ tetracycline. In a preferred embodiment they are doxycyline during the manufacturing process. Following reconstitution or minocycline. of doxycycline hyclate powder for IV administration with sterile water for injection, solutions have a pH of 1.8-3.3. 0439. The mechanism(s) by which doxycycline reduces Tetracyclines and Skin Infections inflammatory lesions (papules and pustules) in patients has 0434 Tetracyclines have been used in ophthalmic oint not been elucidated, but these effects may result at least in part ments for the prevention or treatment of infections of the eye from the anti-inflammatory actions of the drug; other mecha caused by Susceptible bacteria. Although minor skin infec nisms may be involved. tions and wounds usually heal without treatment, some minor 0440 Doxycycline is used for the treatment of rosacea skin wounds do not heal without therapy and it is impossible treatment or prophylaxis of anthrax (including inhalational US 2010/031 0476 A1 Dec. 9, 2010 28 anthrax postexposure), treatment of presumed or confirmed Minocycline Hydrochloride rickettsial infections, including Rocky Mountain spotted 0446 Minocycline hydrochloride is a semisynthetic tetra fever (RMSF), fever, ehrlichiosis, and anaplasmosis, and for cycline antibiotic derived from tetracycline. The drug is usu the treatment of Bartonella infections, for the treatment of ally bacteriostatic in action; it exerts its antimicrobial activity brucellosis, for the treatment of Burkholderia Infections, by inhibiting protein synthesis. It is a yellow crystalline pow Chlamydial Infections, Lymphogranuloma Venereum Psitta der that is sparingly soluble in water, slightly soluble in cosis, Ehrlichiosis and Anaplasmosis, Gonorrhea and Asso alcohol; practically insoluble in chloroform and in ether; ciated Infections, Epididymitis, Proctitis, Granuloma Ingui soluble in solutions of alkali hydroxides and carbonates. pH male (Donovanosis.) Legionella Infections, Leptospirosis, of a solution in water containing the equivalent of minocy Lyme Disease, Prophylaxis of Lyme Disease, Erythema cline 1% is between 3.5 and 4.5. Preparations of minocycline Migrans, Early Neurologic Lyme Disease, Lyme Carditis, or hydrochloride have an acid pH and incompatibility may rea Borrelial Lymphocytoma, Lyme Arthritis, Malaria, and pre sonably be expected with alkaline preparations or with drugs vention, Mycobacterial Infections, Mycobacterium marinum unstable at low pH. Infections, Pelvic Inflammatory Disease, Parenteral Regi 0447. It is highly sensitive and should be stored in airtight mens, Plague, pleural Effusion, Rickettsial Infections, Q containers and protected from light. Therefore use in foam Fever, Syphilis, Tularemia, Treatment, Postexposure Prophy able formulations stored in airtight sealed containers under laxis pressure with propellant may contribute to preserving stabil 0441 When reconstituted and diluted with 0.9% sodium ity Subject to selection of compatible canisters and accesso chloride or 5% dextrose, doxycycline hyclate IV solutions ries containing 0.1-1 mg of doxycycline per mL are stable for 48 0448 Photosensitivity, manifested as an exaggerated Sun burn reaction on areas of the body exposed to direct Sunlight hours at 25°C.; when reconstituted and diluted with Ringer's, or ultraviolet light, has occurred with tetracyclines and 10% invert sugar, Normosol-MR) in D5W, Normosol-R(R) in Minocycline has been associated with pigmentation of the D5W. Plasma-Lyte(R) 56 in 5% dextrose, or Plasma-Lyte(R) skin and other tissues 148 in 5% dextrose, doxycycline hyclate IV solutions con 0449 Minocycline has a spectrum of activity and mode of taining 0.1-1 mg/mL are stable for 12 hours at room tempera action similar to that of tetracycline but it is more active ture. The manufacturer states that doxycycline hyclate Solu against many species including Staphylococcus aureus, tions prepared with any of these infusion solutions are stable streptococci. Neisseria meningitidis, various enterobacteria, for 72 hours at 2-8°C. when protected from direct sunlight Acinetobacter, Bacteroides, Haemophilus, Nocardia, and and artificial light; however, after storage in this manner, Some mycobacteria, including M. leprae. Partial cross-resis infusion of these solutions must be completed within 12 hours tance exists between minocycline and other tetracyclines but Doxycycline hyclate IV solutions diluted to a concentration Some strains resistant to other drugs of the group remain of 0.1-1 mg/mL with lactated Ringer's injection or 5% dex sensitive to minocycline, perhaps because of better cell-wall trose in lactated Ringer's injection must be infused within 6 penetration. Minocycline is a tetracycline derivative with hours to ensure stability. During infusion, all doxycycline uses similar to those of tetracycline. It is also a component of hyclate IV solutions must be protected from direct sunlight. multidrug regimens for the treatment of leprosy and has been (Martindale 2007 Electronic Version). Thus it can be seen that used in the prophylaxis of meningococcal infection to elimi Doxycycline is not stable for more than short periods of a nate the carrier state, but the high incidence of vestibular matter of hours. disturbances means that it is not the drug of choice for the 0442 Preparations of doxycycline hyclate have an acid pH latter. It has neuroprotective properties. It is being investi and incompatibility may reasonably be expected with alka gated for motor neurone disease, for the management of Hun tington's chorea. It is used in the treatment of rheumatoid line preparations or with drugs unstable at low pH. arthritis and in the treatment of various skin disorders, includ 0443 Doxycycline is more active than tetracycline against ing acne. many bacterial species including Streptococcus pyogenes, enterococci, Nocardia spp., and various anaerobes. Cross Additional Therapeutic Agent and Antibiotics resistance is common although some tetracycline-resistant Staphylococcus aureus respond to doxycycline. Doxycycline 0450 Several disorders of the target site (such as the skin, a body Surface, a body cavity, a mucosal Surface, the nose, the is also more active against protozoa, particularly Plasmodium mouth, the eye, the ear canal, the respiratory system, the spp. vagina and the rectum), involve a combination of etiological 0444 Doxycycline is a tetracycline derivative with uses factors, some of which are related to a microbiological infec similar to those oftetracycline. It may sometimes be preferred tion (that can be affected by an antibiotic agent); and other to other tetracyclines in the treatment of susceptible infec etiological factors that require an additional therapeutic tions because of its fairly reliable absorption and its long modality. For example, impetigo involves bacterial infection half-life that permits less frequent (often once daily) dosing. as well as inflammation, and therefore combined treatment It also has the advantage that it can be given (with care) to with an antibiotic agent and an anti-inflammatory agent patients with renal impairment. However, relatively high would be beneficial. Likewise, chronic ulcers involve poor doses may need to be given for urinary-tract infections blood Supply and potential bacterial, fungal and viral infec because of its low renal excretion. tions, which warrants a beneficial effect of a combination of 0445 For relapsing fever and louse-borne typhus, for the an antibiotic agent and a vasoactive agent. prophylaxis of leptospirosis, for periodontiti, for Lymphatic 0451 Additional non-limiting examples of combinations filariasis, for Musculoskeletal and joint disorders and for the of an antibiotic agent and an additional active agent are pro treatment of acne. vided in the following table: US 2010/031 0476 A1 Dec. 9, 2010

Disorder Exemplary Additional Active Agent 80l. At least one agent selected from the group consisting of a retinoid; a keratolytic acid, an alpha-hydroxy acid and derivatives thereof, a beta-hydroxy acid and derivatives thereof, a skin-drying agent, an anti-seborrhea agent, a corticosteroid and a non-steroidal anti-inflammatory agent. Rosacea. At least one agent selected from the group consisting of a retinoid; a keratolytic acid, an alpha-hydroxy acid, a beta-hydroxy acid and derivatives thereof. Otitis At least one agent selected from the group of an antifungal agent, a local anesthetic agent, a corticosteroid and a non-steroidal anti-inflammatory agent. Psoriasis At least one agent selected from the group consisting of a corticosteroid, coal tar, anthralin and a photodynamic therapy agent

0452 Hence, in many cases, the inclusion of an additional infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, therapeutic agent in the foamable composition of the present acute lymphangitis, lymphadenitis, erysipelas, cutaneous disclosure, contributes to the clinical activity of the antibiotic abscesses, necrotizing Subcutaneous infections, Scalded skin agent. syndrome, folliculitis, furuncles, hidradenitis Suppurativa, 0453 Thus, in one or more embodiments, the foamable carbuncles, paronychial infections, rashes, erythrasma, impe composition further includes at least one additional therapeu tigo, eethyma, yeast skin infections, warts, molluscum con tic agent, in a therapeutically effective concentration. tagiosum, trauma or injury to the skin, post-operative or post 0454. In one or more embodiments, the at least one addi Surgical skin conditions, Scabies, pediculosis, creeping tional therapeutic agent is selected from the group consisting eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, of a steroidal antiinflammatory agent, a nonsteroidal anti pityriasis rubra pilaris, edematous, erythema multiforme, inflammatory drug, an immunosuppressive agent, an immu erythema nodosum, grannuloma annulare, epidermal nomodulator, an immunoregulating agent, a hormonal agent, necrolysis, Sunburn, photosensitivity, pemphigus, bullous an antifungal agent, an antiviral agent, an antiparasitic agent, pemphigoid, dermatitis herpetiformis, keratosis pilaris, cal a vasoactive agent, a vasoconstrictor, a vasodilator, VitaminA, louses, corns, ichthyosis, skin ulcers, ischemic necrosis, mil a vitamin A derivative, vitamin B, a vitamin B derivative, iaria, hyperhidrosis, moles, Kaposi's sarcoma, melanoma, vitamin C, a vitamin C derivative, vitamin D, a vitamin D malignant melanoma, basal cell carcinoma, squamous cell derivative, vitamin E, a vitamin E derivative, vitamin F, a carcinoma, poison ivy, poison oak, contact dermatitis, atopic vitamin F derivative, vitamin K, a vitamin K derivative, a dermatitis, rosacea, purpura, moniliasis, candidiasis, bald wound healing agent, a disinfectant, an anesthetic, an anti ness, alopecia, Behcet's syndrome, cholesteatoma, Dercum allergic agent, an alpha hydroxyl acid, lactic acid, glycolic disease, ectodermal dysplasia, gustatory Sweating, nail acid, a beta-hydroxy acid, a protein, a peptide, a neuropep patella syndrome, lupus, hives, hair loss, Hailey-Hailey dis tide, a allergen, an immunogenic Substance, a haptene, an ease, chemical or thermal skin burns, Scleroderma, aging oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic skin, wrinkles, Sun spots, necrotizing fasciitis, necrotizing acid, sebacic acid, adipic acid, fumaric acid, an antibiotic myositis, gangrene, Scarring, and vitiligo. agent, an antiproliferative agent, an anticancer agent, a pho todynamic therapy agent, an anti-wrinkle agent, a radical 0457. Likewise, the foamable composition of the present Scavenger, a metal oxide (e.g., titanium dioxide, Zinc oxide, disclosure is suitable for treating a disorder of a body cavity or Zirconium oxide, iron oxide), silicone oxide, an anti wrinkle mucosal Surface, e.g., the mucosa of the nose, mouth, eye, ear, agent, a skin whitening agent, a skin protective agent, a mask respiratory system, vagina or rectum. Non limiting examples ing agent, an anti-wart agent, a refatting agent, a lubricating of Such conditions include chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papilloma agent and mixtures thereof. virus (HPV), genital warts, bacterial vaginosis, candidiasis, Fields of Applications chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscum con 0455 The foamable carrier of the present disclosure is tagiosum, nongonococcal urethritis (NGU), trichomoniasis, Suitable for treating any infected Surface. In one or more Vulvar disorders, Vulvodynia, Vulvar pain, yeast infection, embodiments, foamable carrier is suitable for administration vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), con to the skin, a body Surface, a body cavity or mucosal Surface, tact dermatitis, pelvic inflammation, endometritis, salpingi e.g., the cavity and/or the mucosa of the nose, mouth, eye, ear, tis, oophoritis, genital cancer, cancer of the cervix, cancer of respiratory system, vagina or rectum (severally and inter the Vulva, cancer of the vagina, vaginal dryness, dyspareunia, changeably termed herein “target site'). anal and rectal disease, anal abscess/fistula, anal cancer, anal 0456 By selecting a suitable active agent, or a combina fissure, anal warts, Crohn's disease, hemorrhoids, anal itch, tion of at least two active agents, the foamable composition of pruritus ani, fecal incontinence, constipation, polyps of the the present disclosure is useful in treating an animal or a colon and rectum. human patient having any one of a variety of dermatological 0458 In an embodiment of the present disclosure, the disorders, including dermatological pain, dermatological composition is useful for the treatment of an infection. In one inflammation, acne, acne Vulgaris, inflammatory acne, non or more embodiments, the composition is suitable for the inflammatory acne, acne fulminans, nodular papulopustular treatment of an infection, selected from the group of a bacte acne, acne conglobata, dermatitis, bacterial skin infections, rial infection, a fungal infection, a yeast infection, a viral fungal skin infections, viral skin infections, parasitic skin infection and a parasitic infection. US 2010/031 0476 A1 Dec. 9, 2010 30

0459. In an embodiment of the present disclosure, the 0466 Conversely by chemical stability of one or more composition is useful for the treatment of wound, ulcer and active agents is meant that at least one of the one or more burn. This use is particularly important since the composition active agents is less Susceptible to one or more of inter alia of the present disclosure creates a thin, semi-occlusive layer, reaction, breakdown, ionization or oxidation or the rate which coats the damaged tissue, while allowing exudates to thereof is impeded when incorporated into a pharmaceutical be released from the tissue. or cosmetic carrier that is non aqueous or Substantially non 0460. The composition of the present disclosure is also aqueous. Suitable for administering a hormone to the skin or to a 0467 “Chemically stable' or “chemical stability” may be mucosal membrane or to a body cavity, in order to deliver the defined as demonstrating Substantially no or minimal break hormone into the tissue of the target organ, in any disorder down from oxidation 72 hours after mixing with the carrier or that responds to treatment with a hormone. agent when stored at about at least 25°C. Substantially no or 0461. In light of the hygroscopic nature of the composi minimal breakdown may be determined using HPLC meth tion, it is further suitable for the treatment and prevention of ods disclosed herein or other methods, where the mass of the post-Surgical adhesions. Adhesions are Scars that form abnor compound is determined at time 0 (i.e., within about 1 hour mal connections between tissue surfaces. Post-Surgical adhe after mixing with the carrier or foamable pharmaceutical sion formation is a natural consequence of Surgery, resulting composition) and about 72 hours after mixing, and wherein at when tissue repairs itself following incision, cauterization, least about 90% by mass of the compound is detected at about Suturing, or other means of trauma. When comprising appro 72 hours compared to time 0. Alternatively, degradation prod priate protective agents, the foam is Suitable for the treatment ucts may be determined using HPLC methods disclosed or prevention of post Surgical adhesions. The use of foam is herein or other methods, where the mass of the degradation particularly advantageous because foam can expand in the products is determined at time 0 and about 72 hours after body cavity and penetrate into hidden areas that cannot be mixing, and wherein less than about 1% by mass of the reached by any other alternative means of administration. compound in the mixture is degradation products. When the compound is minocycline, a suitable degradation product for Substantially Alcohol-Free purposes of determining “chemical stability” or “chemically 0462 According to one or more embodiments, the foam stable' is 4-epiminocycline. able composition is substantially alcohol-free, i.e., free of 0468. Other foamable compositions are described in: U.S. short chain alcohols. Short chain alcohols, having up to 5 Publication No. 05-0232869, published on Oct. 20, 2005, carbonatoms in their carbon chain skeleton and one hydroxyl entitled NONSTEROIDAL IMMUNOMODULATING KIT group, such as ethanol, propanol, isopropanol, butaneol, iso AND COMPOSITION AND USES THEREOF; U.S. Publi butaneol, t-butaneol and pentanol, are considered less desir cation No. 05-0205086, published on Sep. 22, 2005, entitled able solvents or solvents due to their skin-irritating effect. RETINOIDIMMUNOMODULATINGKITAND COMPO Thus, the composition is Substantially alcohol-free and SITION AND USES THEREOF; U.S. Publication No. includes less than about 5% final concentration of lower 06-0018937, published on Jan. 26, 2006, entitled STEROID alcohols, preferably less than about 2%, more preferably less KIT AND FOAMABLE COMPOSITION AND USES than about 1%. THEREOF; U.S. Publication No. 05-0271596, published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSI Shakability TION AND USES THEREOF; U.S. Publication No. 06-0269485, published on Nov.30, 2006, entitled ANTIBI 0463 Shakability means that the composition contains OTIC KIT AND COMPOSITION AND USES THEREOF: some or sufficient flow to allow the composition to be mixed U.S. Publication No. 07-0020304, published on Jan. 25, or remixed on shaking. That is, it has fluid or semi fluid 2007, entitled NON-FLAMMABLE INSECTICIDE COM properties. In some very limited cases it may still be possible POSITION AND USES THEREOF; U.S. Publication No. to have a foamable composition which is flowable but not 06-0193789, published on Aug. 31, 2006, entitled FILM apparently shakable. FORMING FOAMABLE COMPOSITION: U.S. Publica tion No. 2007-0292355 published on Dec. 20, 2007 and Breakability entitled ANTI-INFECTION AUGMENTATION OF FOAM 0464 A breakable foam is thermally stable or substan ABLE COMPOSITIONS AND KITANDUSESTHEREOF: tially so, yet breaks under sheer force. The breakable foam of U.S. Publication No. 2008-0069779 and entitled DICAR the present disclosure is not "quick breaking’, i.e., it does not BOXYLICACID FOAMABLEVEHICLE AND PHARMA readily collapse upon exposure to body temperature environ CEUTICAL COMPOSITIONS THEREOF; U.S. Publica ment. Sheer-force breakability of the foam is clearly advan tion 20080206159, published on Aug. 28, 2008 and entitled tageous over thermally induced breakability, (due to, for COMPOSITIONS WITH MODULATING AGENTS; U.S. example, the presence of alcohol) since it allows comfortable patent application Ser. No. 1 1/767,442, filed on Jun. 22, 2007, application and well directed administration to the target area. entitled FOAMABLE COMPOSITIONS AND KITS COM PRISING ONE OR MORE OF A CHANNEL AGENT, A Chemical Instability and Stability CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, AND RELATED AGENTS AND THEIR USES: U.S. Publi 0465 By chemical instability of one or more active agents cation 2008-0069779, published on Mar. 20, 2008 and is meant that at least one of the one or more active agents is entitled FOAMABLE VEHICLE AND VITAMIN AND Susceptible to one or more of interalia reaction, breakdown, FLAVONOID PHARMACEUTICAL COMPOSITIONS ionization or oxidation or the rate thereof is increased when THEREOF, all of which are incorporated herein by reference incorporated into a pharmaceutical or cosmetic carrier that is in their entirety. More particularly any of the active ingredi non aqueous or substantially non aqueous. ents; the solvents; the Surfactants; foam adjuvants; penetra US 2010/031 0476 A1 Dec. 9, 2010

tion enhancers; humectants; moisturizers; and other excipi cooling as appropriate for specific polymer and add to ents as well as the propellants listed therein can be applied the oily mixture under vigorous mixing at ~40°C. herein and are incorporated by reference. 0485. Note that for substantially waterless foam a small 0469. The present disclosure is described with reference to amount of water is added step 5. For more details of proce the following examples. This disclosure is not limited to these dures please see the specific descriptions in the Examples. examples and experiments. Many variations will suggest themselves and are within the full intended scope of the appended claims. Production Under Vacuum 0486 Optionally, the foamable formulation may be pro Methodology duced under nitrogen and under vacuum. Whilst the whole 0470 The formulas of the present disclosure may be made process can be carried out under an oxygen free environment, in the following general way with appropriate adjustments for it can be sufficient to apply a vacuum after heating and mixing each formulation as will be appreciated by someone skilled in all the ingredients to obtain an emulsion or homogenous the art. Polymers, ifany, are mixed, swelled and solubilized in liquid. Preferably the production chamber is equipped to the waterless medium, when necessary, with appropriate heat apply a vacuum but if not the formulation can be for example until it forms a clear solution. Stabilizing surfactants added placed in a dessicator to remove oxygen prior to filing and usually with heat, until a homogeneous mixture is obtained, crimping. the mixture is then allowed to cool. The remainder of the ingredients, are then added with mixing until they have dis Canisters Filling and Crimping Solved in the medium. The active agent is usually added at the 0487. Each aerosol canister is filled with PFF and crimped end once the modulating agent, if present, has been incorpo with valve using vacuum crimping machine. The process of rated. For foam the canisters are then filled with the above applying a vacuum will cause most of the oxygen present to waterless formula, sealed and crimped with a valve and pres be eliminated. Addition of hydrocarbon propellant may with surized with the propellant. out being bound by any theory further help to reduce the 0471. A general procedure for preparing foamable com likelihood of any remaining oxygen reacting with the active positions is set out in WO 2004/037225, which is incorpo ingredient. It may do so, without being bound by any theory, rated herein by reference. by one or more of dissolving in the oil or hydrophobic phase of the formulation, by dissolving to a very limited extent in Waterless Foam the aqueous phase, by competing with Some oxygen from the 0472. 1. Dissolve the polymers, if any, in the main sol formulation, by diluting out any oxygen, by a tendency of vent with heating or cooling as appropriate for specific oxygen to occupy the dead space, and by oxygen occupying polymer. Add the all other ingredients and heat to 75°C. part of the space created by the vacuum being the unfilled to melt and dissolve the various ingredients. Volume of the canister or that remaining oxygen is rendered 0473 2. Cool to below 40° C. and add sensitive ingre substantially ineffective in the formulation. dients with mild mixing. 0488 Pressurizing 0474 3. Cool to room temperature. 0489. Propellant Filling 0475. Note that for substantially waterless foam a small 0490 Pressurizing is carried out using a hydrocarbon gas amount of water is added before step 2. orgas mixture. Canisters are filled and then warmed for 30sec in a warm bath at 50° C. and well shaken immediately there Oily Waterless Foam after. 0476 1. Mix all ingredients excluding polymers and 0491 Closure Integrity Test. heat to 75° C. to melt and dissolve and obtain homoge 0492 Each pressurized canister is subjected to bubble and neous mixture. crimping integrity testing by immersing the canister in a 60° 0477 2. Mix well and cool to below 40° C. and add the C. water bath for 2 minutes. Canisters are observed for leak polymers, if any, and sensitive ingredients with moder age as determined by the generation of bubbles. Canisters ate mixing. releasing bubbles are rejected. 0478. 3. Cool to room temperature. 0479. Note that for substantially waterless foam a small Tests amount of water is added before step 2. Oily Foam with Phospholipids 0493 By way of non limiting example the objectives of 0480) 1. Swell the phospholipids in the main oily sol hardness, collapse time and FTC stability tests are briefly set vent under mixing for at least 20 minutes until uniform out below as would be appreciated by a person of the art. Suspension is obtained. 0481 2. Add all other ingredients excluding polymers Hardness and heat to 75° C. to melt and dissolve and obtain homo 0494 LFRA100 instrument is used to characterize hard geneous mixture. ness. A probe is inserted into the test material. The resistance 0482. 3. Mix well and cool to below 40° C. and add the of the material to compression is measured by a calibrated polymers, if any, and sensitive ingredients with moder load cell and reported in units of grams on the texture analyzer ate mixing. instrument display. Preferably at least three repeat tests are 0483 4. Cool to room temperature. made. The textural characteristics of a dispensed foam can 0484 5. In case of polymers dissolved or organic sol affect the degree of dermal penetration, efficacy, spreadability vent, dissolve the polymers in the solvent with heating or and acceptability to the user. The results can also be looked at US 2010/031 0476 A1 Dec. 9, 2010 32 as an indicator of softness. Note: the foam sample is dis pensed into an aluminum sample holder and filled to the top of -continued the holder. Detector: UV at 254 mm Injection volume: 10 IL Collapse Time Autosampler temp.: 5° C. Column temp.: 40° C. 0495 Collapse time (CT) is examined by dispensing a Mobile phase: 78 buffer: 22 ACN given quantity of foam and photographing sequentially its Diluent: 6S buffer: 35 ACN appearance with time during incubation at 36°C. It is useful Approximate RT: 11.5 min for minocycline HCI for evaluating foam products, which maintain structural sta 8 min for 4-epiminocycline bility at skin temperature for at least 1 min. Viscosity ii) Doxycycline (Dox) Formulations: 0496 Viscosity is measured with Brookfield LVDV-II+ 0502. About 1 g of pre-foam formulation or foam is PRO with spindle SC4-25 at ambient temperature and 10, 5 weighed into 50 ml plastic centrifuge tube. 25 ml of 0.01N and 1 RPM. Viscosity is usually measured at 10 RPM. How HCl (diluent) and 15 ml of dichloromethane are added. The ever, at about the apparent upper limit for the spindle of mixture is shaken for 1 hour an inverted shaker stand and ->50,000 CP, the viscosity at 1 RPM may be measured, thereafter centrifuged for 5 minutes at 4000 rpm. The super although the figures are of a higher magnitude. natant is separated by vacuum pump and filtered thereafter through a 0.45um PTFE+GL filter. The first few drops of the FTC (Freeze Thaw Cycles) filtrate are discarded. The resultant clear solution layer is 0497 To check the foam appearance under extreme con sampled and injected into an HPLC, using a C-8 column. The ditions of repeated cycles of cooling, heating, (first cycle) content of MCH is calculated against DOX prepared in 1g cooling, heating (second cycle) etc., commencing with -100° placebo with AN 0.2 mg/mL standard. C. (24 hours) followed by +400°C. (24 hours) measuring the 0503. The details of the method conditions are as follows: appearance and again repeating the cycle for up to three times. Column: Thermo Hypersil GOLD C-8 250x4.6 mm 5L cat: Chemical Stability 252O5-25463.O. 0498. The amount of active agent present is analyzed in 0504 Column temp: 35° C. foam expelled from various pressurized canisters containing Flow 1.0 ml/min, foam formulations using HPLC. Analysis is carried out at Injection volume 10 uL. Zero time and at appropriate time intervals thereafter. The canisters are stored in controlled temperature incubators at 5° Detector: UV at 270 nm. C., at 25°C., at, 40° C. and at 50° C. At appropriate time (0505 Gradient for 25 min with post time: 15 min. intervals canisters are removed and the amount of active agent in the foam sample is measured. Visual Stability Tests Analysis Spillability 0499 Analysis of Antibiotic Concentrations in Formula 0506. In most formulations, addition of Minocycline HCl tions per se causes to loss of fluidity (the formulation becomes a thickened mass). This is undesirable phenomenon. Therefore i) Minocycline Formulations: an objective in designing lead formulations it to formulate so the compostion does not lose fluidity, and stays spillable after 0500 About 0.5 g foam or pre-foam formulation is dis the incorporation of active agent. Spillability means free solved with diluent (65% phosphate buffer: 35% Acetonitrile moving or rotating of formulation inside the glass bottle upon (ACN)) in a 25 mL volumetric flask. The sample is shaken for inversion. 30 min on an inverted shaker stand for 10 min at room tem perature. The resulting Suspension is centrifuged for 5 min Chemical Oxidation utes at 4000 rpm. The supernatant is separated by vacuum pump and filtered thereafter through a 0.45 um PTFE--GL 0507 Chemical oxidation of the active ingredient in the filter. The first few drops of the filtrate are discarded. The foam formulation can be noticed visually (e.g. changing the resultant clear solution layer is analyzed by HPLC using color from yellow to orange). See color test. Oxidation results columnRP-8. The content of MCH is calculated against an in a lower assay. Degradation of minocycline can be an MCH standard 0.4 mg/mL (concentration). The content of epimerization chemical process (4-epiminocycline). 4-epiminocycline is calculated against MCH standard 0.02 mg/mL (concentration). Bubble Size 0501. The details of the method conditions are as follows: 0508 Foams are made of gas bubbles entrapped in liquid. The bubble size and distribution reflects in the visual texture and smoothness of the foam. Foam bubbles size is determined by dispensing a foam sample on a glass slide, taking a picture Column: Purosphere STARRP-8 endcapped 51 Merck 250 x Cat. 4.6 of the foam Surface with a digital camera equipped with a 1...SOO32.OOO1 macro lens. The diameter of about 30 bubbles is measured Flow: 1.2 mL/min manually relatively to calibration standard template. Statisti cal parameters such as mean bubble diameter, standard devia US 2010/031 0476 A1 Dec. 9, 2010 tion and quartiles are then determined. Measuring diameter tions comprising a single phase since the Suspensions will may also be undertaken with image analysis Software. The sediment and as there is not an emulsion the formulations can camera used was a Nikon D40X Camera (resolution 10 MP) more readily separate. equipped with Sigma Macro Lens (ref: APO MACRO 150 mm F2.8 EX DG HSM). Pictures obtained are cropped to 2. Procedure keep a squared region of 400 pixelsx400 pixels. 0516 2.1 Following preparation of the experimental 0509 Microscope Size: formulation/s, allow to stand at room temperature for 24 h. 0510. The light microscope enables observing and mea 0517 2.2 Handle pentane in the chemical hood. Add to Suring particles from few millimeters down to one micron. each experimental formulation in a 20-mL glass vial a Light microscope is limited by the visible light wavelength quantity of pentane equivalent to the specified quantity and therefore is useful to measuring size of particles above of propellant for that formulation, mix and allow formu 800 nanometers and practically from 1 micron (1,000 nanom lation to stand for at least 1 h and not more than 24 h. eters). 0518 2.3 Transfer each mixture to 1.5 mL microtubes. Tap each microtube on the table surface to remove Color entrapped air bubbles. 0519 2.4 Place visually balanced microtubes in the 0511 Color is tested by visual observation and in particu centrifuge rotor and operate the centrifuge at one or lar by comparison to “Pantone(R) formula guide solid more of 10,000 rpm for 10 min, 3,000 rpm for 10 minor uncoated colors. The preferable color is Yellow-bright yel at 1,000 rpm for 10 min. low 600U-601 U-602U according to the Pantone acceptable colors. Minocycline changes color to orange/greenish with Uniformity oxidation or complexation. These oxidized colors are not Intra-Canister Uniformity desirable. Colors Such as 609U/608U/61OU are indicative of degradation by the tetracycline antibiotic. 0520 1. Representative product containers are collected, sample test Solutions are prepared and the content of the analyte is determined according to standard methods in the Shakability art. Variability of content is characterized as percent dif 0512 Shakability represents the degree to which the user ference or relative standard deviation, as appropriate, according to the number of samples evaluated. is able to feel/hear the presence of the liquid contents when 0521. 2. The results ascertain variability or uniformity the filled pressurized canister is shaken. Shaking is with nor within a given container in content of analytes (primarily mal mild force without vigorous shaking or excessive force. active pharmaceutical ingredients, but also preservatives) When the user cannot sense the motion of the contents during taken from different parts of a pressurized canister drug shaking the product may be considered to be non shakable. products This property may be of particular importance in cases where 0522. 3. Two full canisters were shaken according to prod shaking is required for affecting proper dispersion of the uct instructions. About 1-3 g of Foam was dispensed from COntentS. each canister and discarded. Foam sufficient for two repli cate sample solution preparations was then dispensed into Shakability Scoring: a glass beaker. This represents the initial sample. A middle portion is then dispensed from each canister being about 0513 half the canister contents. This middle dispensed portion may be discarded or collected for testing purposes, as necessary. Foam Sufficient for two replicate sample solu Shakability tion preparations was then dispensed into a glass beaker. Good shakability (conforms to required quality specification) 2 This represents the final sample. A small amount of formu Moderate shakability (conforms to required quality specification) 1 lation remains in the canister. The foam samples were Not shakable (fails to meet required quality specification) but may O stirred to remove gas/air bubbles. From both the initial and still be flowable and allow foam formation of quality final foam portions from each canister 4 separate sample Is Substantially notable to pass through valve Block Solutions are prepared and analyzed, 2 from the initial portion and 2 from the final portion. The percent difference is calculated as follows: Centrifugation 0514 Aging by centrifugation: Difference between content determined in initial & final portions x 100 1. Principle of Test Mean of content of initial & final portions 0515. The centrifugation used in this procedure serves as a stress condition simulating the aging of the liquid dispersion 0523 and the intra canister uniformity evaluated from the under investigation. Under these conditions, the centrifugal results. force applied facilitates the coalescence of dispersed globules or sedimentation of dispersed solids, resulting in loss of the Stock Compositions desired properties of the formulated dispersion. The test may 0524 Non-limiting examples of how stock solutions are be less meaningful for waterless Suspensions and composi made up with and without API are illustrated. Other stock US 2010/031 0476 A1 Dec. 9, 2010 34

Solutions may be made using the same methodology by sim virtually negligible. This disclosure is not limited to these ply varying adding or omitting ingredients as would be appre examples and experiments. Many variations will Suggest ciated by one of the ordinary skills in the art. themselves and are within the full intended scope of the appended claims. Examples 0526. Two major groups of experiments were performed to find Suitable topical formulations comprising either 0525. The present disclosure is described with reference to minocycline (minocycline hydrochloride) or doxycycline the following examples. For the purpose of the Examples (“DOX') (doxycycline hyclate or monohydrate). below it was sufficient to apply a vacuum only at the crimping 0527 Table A shows at least some of the components used stage although for long term stability preferably any vacuum in formulating minocycline hydrochloride (“MCH) and should be applied during manufacture as well at a sufficient Table B shows some of the components used in formulating pressure so that any oxygen remaining in the formulation is doxycycline hyclate.

TABLE A Components used in formulating carriers and compositions for Minocycline hydrochloride MCH Anti-greasiness foam adjuvant emollients Oils agent Surfactants Glycerol Oleyl alcohol Cyclomethicone Light Aluminum Starch nonOStearate mineral oil Octenylsuccinate (ASOS) Polysorbate Stearyl alcohol PPG-15 Stearyl Hydrogenated 60 Ether Castor Oil Polysorbate Myristyl alcohol Octyldodecanol 8O Sucrose Cocoglycerides Isohexadecanol distearate Steareth Diisopropyl 2(Polyoxyl 2 adipate Stearyl Ether) Steareth Cetearyl 20(Polyoxyl Octanoate 20 Stearyl Ether) Steareth 21 (Polyoxyl 21 Stearyl Ether) Sorbitan nonOStearate

Glucose Sesquistearate Myr 52(Polyoxyl 40 stearate) Myr 59(Polyoxyl 100 stearate) Montanov S (cetearyl alcohol and coconut alcohol) Glyceryl nonOStearate Sepige 305 (Polyacryl amide + isoparaffin + Laureth-7) Full list

Titanium Dioxide Cyclomethicone PPG-15 Stearyl Ether US 2010/031 0476 A1 Dec. 9, 2010 35

TABLE A-continued Components used in formulating carriers and compositions for Minocycline hydrochloride MCH Anti-greasiness foam adjuvant emollients Oils agent Octyldodecanol Light mineral oil Oleyl alcohol Isohexadecanol Glycerol nonOStearate Diisopropyl adipate Stearyl alcohol Myristyl alcohol Hydrogenated Castor Oil Polysorbate 60.80 Cetearyl Octanoate? Sucrose distearate Steareth 20(Polyoxyl 20 Stearyl Ether) Steareth 2 (Polyoxyl 2 Stearyl Ether) Aluminum Starch Octenylsuccinate Cocoglycerides Sorbitan nonOStearate (Span 60) Metyl Glucose Sesquistearate Myr 52(Polyoxyl 40 stearate) Myr 59(Polyoxyl 100 stearate) Montanov S(cetearyl alcohol and coconut alcohol) Carbopol 934 Minocycline HCL Sepigel 305 (Polyacryl amide + isoparaffin + Laureth-7) Bentone PTM Bentone WS 5 PCV Ethioce 7FP Ethocel 100 FP Aerosil Dry-flo AF Glyceryl nonOStearate US 2010/031 0476 A1 Dec. 9, 2010 36

TABLE B Components used in formulating compositions for doxycycline hyclate.

DOX

foam Anti adjuvants emollients Oils greasiness Surfactants Glycerol Oleyl alcohol Cyclomethicone Light Mineral Oil Aluminum nonOStearate Starch Octenylsuccinate (ASOS) Sucrose Ester Stearic acid PPG-15 Stearyl MCT oil HLB 11 Ether GMS-PEG 1 OO Stearyl alcohol Propylene Stearate Glycol Polysorbate 80 Myristyl alcohol Octyldodecanol Polysorbate 60 Cocoglycerides Glycerol Polysorbate 20 Diisopropyl adipate Sorbitan Cetearyl nonOStearate Octanoate Methy Glucose Sesquistearate PEG 40 Stearate (Myri 52) PEG 1 OO Stearate (Myri 59) Hydrogenated Castor Oil Steareth-2 Steareth-20 Steareth-21 Poloxamer 407 (20% gel) Full list Cyclomethicone PPG-15 Stearyl Ether Propylene Glycol Oleyl alcohol Cetearyl Octanoate Octyldodecanol Light Mineral Oil Glycerol Klucel EF Stearic acid Stearyl alcohol Myristyl alcohol Glycerol nonOStearate Sucrose Ester HLB 11 GMS-PEG 1 OO Stearate Cocoglycerides Methocel A4 Xanthan Gum Polysorbate 80 Polysorbate 60 Polysorbate 20 Sorbitan nonOStearate Methy Glucose Sesquistearate PEG 40 Stearate (Myri 52) PEG 1 OO Stearate (Myri 59) Hydrogenated Castor Oil US 2010/031 0476 A1 Dec. 9, 2010 37

TABLE B-continued Components used in formulating compositions for doxycycline hyclate.

DOX

foam Anti adjuvants emollients Oils greasiness Steareth-2 Steareth-20 MCT oil Steareth-21 Aluminum Starch octenylsuccinate (ASOS) Diisopropyl adipate Poloxamer 407 (20% gel) Dry-Flo AF Aerosil Ethioce 7 FP Doxycycline Hyclate Doxycycline Monohydrate

0528 A list of the chemical constituents of the Brand of the propellant and expelled from a pressurized canister, has names of Some of the ingredients of the present disclosure, the following property: used in some of the formulations of the present disclosure 0531 a foam quality of at least good up to excellent; appears in the following "Ingredients Table’ Table C. 0532 and at least one of the following properties: 0533 specific gravity in the range of about 0.02 gr/mL INGREDIENTS TABLE C to about 0.5 gr/mL: 0534 a foam texture of a very fine creamy foam con Name Brand name sistency to a fine bubble structure consistency; PPG-15 Stearyl Ether Sympatens ASP/150 0535 a sustainability of more than 95% for at least one Octyldodecanol Eutanol GPH minute upon release thereof to a Surface from an aerosol Light mineral oil Pioner 2076P Cyclomethicone DC 345 fluid Can, Diisopropyl adipate Soadipate 0536 less than 20% sedimentation following ten min Oleyl Alcohol HD-EUTANOLVPH utes of centrifugation at 3000 g; and Glyceryl monostearate Cltina GMSWPH Stearyl alcohol Speziol C18 PH 0537 compatibility with said at least one unstable Hydrogenated Castor Oil Cutina HRPH active agent, wherein said compatibility is defined as Cetearyl Octanoate Levitol EHO less than 20% oxidation of said at least one unstable Polyoxyl 20 stearyl Ether Brij 78 P active agent. Polyoxyl 2 stearyl Ether Brij 72 Myristyl Alcohol Speziol C14 0538. As can be seen in Table 1, the DOX-001 formulation Methylglucose sesquistearate Tego Care PS was only FG (fairly good) and therefore did not meet the Aluminum starch octenylsuccinate Dry flo Plus quality standard. Experimental steps were performed, includ (ASOS) ing: Cocoglycerides Nowata. A Doxycycline Hyclate Doxycycline Hyclate 0539 other additives to improve foam quality Propellant PIB 1681 0540 change of surfactants and polymers to improve foam quality. 0541. Thus, as can be seen in Table 1, the foam quality was improved from fairly good to good from batch DOX-001 to EXAMPLES DOX-017 (see Table 22 for additional formulations). Example 1 TABLE 1 Foamable Carriers for Doxycycline Hyclate/Mono Development of a foamable carrier for doxycycline hyclate. hydrate Lot:

0529. Foamable carriers were prepared as follows: DOX-001 DOX-010 DOX-013 DOX-017 0530 Prefoam formulations (PFFs) were prepared % Wiw % Wiw % Wiw % Wiw according to a typical protocol (exemplified for DOX-026, Cyclomethicone 1.49 2.00 3.00 3.00 See Section “General Manufacturing Procedure for DOX PPG-15 Stearyl Ether 9.90 8.00 1S.OO 1S.OO formulations' hereinbelow). Numerous changes were made Propylene Glycol 58.91 to the composition in order to find a PFF which, after addition US 2010/031 0476 A1 Dec. 9, 2010

TABLE 1-continued TABLE 1-continued Development of a foamable carrier for doxycycline hyclate. Development of a foamable carrier for doxycycline hyclate.

Lot: Lot:

DOX-001 DOX-010 DOX-013 DOX-017 DOX-001 DOX-010 DOX-013 DOX-017 % Wiw % Wiw % Wiw % Wiw % Wiw % Wiw Oleyl alcohol 9.90 9.70 1O.OO Shakability NT 2 2 2 Cetearyl Octanoate 3.00 2.00 Collapse Time (s) NT NT 150 240 Octyldodecanol 9.70 12.00 12.00 Hardness(g) NT NT 1423 23.05 Light Mineral Oil 17.84 16.84 Viscosity (cPs) NT NT 1213 4700 Glycerol S1.2O 10 RPM Stearic acid 1.98 Density (g/ml) NT NT Not tested O.168 Stearyl alcohol 1.OO 4.OO 6.OO Myristyl alcohol 1.98 1.00 2.50 FG-fairly good foam quality GMS (glycerol 2.OO 4.OO 6.OO G—Good foam quality monostearate) NT—not tested due to fairly good foam quality Sucrose Ester HLB 11 2.OO Cocoglycerides 6.OO 0542 Comments: It was observed that the combination of Polysorbate 20 O.90 two Surfactants glycerol monostearate and methyl glucose Methy Glucose 3.00 sesquistearate with foam adjuvants provided an improvement Sesquistearate in foam quality. DOX-013 and DOX-017 showed good foam Hydrogenated Castor 1...SO 3.SO Oil quality. In contrast fairly good quality was observed in for Steareth-2 4.95 1...SO S.OO mulations DOX-001 and DOX-010. However, formulations Steareth-20 2.50 13 and 17 when subject to centrifugation at 3000 rpm or Aluminum Starch 1O.OO 10,000 rpm for 10 mins resulted in sedimentation of the Octenylsuccinate Suspension and some separation. (ASOS) (0543. Formulations DOX-001, DOX-017, DOX-010 and Diisopropyl adipate 9.90 9.OO 8.00 8.OO DOX-013 were prepared by heating of oils to 65-70° C. and Doxycycline Hyclate O.99 1.16 1.16 addition of Surfactants by mixing. The mixture was cooled down to 55-60° C. and emollients were added by thorough Control 100.00 100.00 100.00 100.00 mixing. Aluminum Starch Octenylsuccinate was added to Propellant 1681 8.OO 8.00 1O.OO DOX-010 and DOX-013 at 40° C. After homogenization all Control II 108.00 108.00 108.00 110.OO the formulations were cooled down to the room temperature. Date manufacture Jan. 23 Feb. 15 May 8 May 21 API was added with stirring when the temperature fell below Foam quality FG FG G G 30° C. separated 0544 Tables 2 to 4 shows further development of foam at room able carrier for doxycycline, in which the concentrations of temperature Surface active agents and the types of Surface active agents were changed.

TABLE 2 Further Development of a foamable carrier for doxycycline hyclate and doxycycline monohydrate

Lot:

DOX-O22 DOX-O2S DOX-026 DOX-027 DOX-033 % Wiw % Wiw % Wiw % Wiw % Wiw Cyclomethicone 3.00 3.00 3.00 3.00 3.00 PPG-15 Stearyl 1S.OO 1S.OO 1S.OO 1S.OO 1S.OO Ether Oleyl alcohol 1O.OO 1O.OO 1O.OO 10.00 NA Cetearyl Octanoate NA NA 2.OO NA NA Octyldodecanol 12.00 12.00 12.00 12.00 12.00 Light Mineral Oil 26.33 28.96 17.84 18.00 54.46 Stearyl alcohol 4.OO 4.OO 4.OO 6.OO 6.OO Myristyl alcohol 1.OO 1.OO 1.OO 2.50 2.50 Glycerol 4.OO 3.00 4.OO 6.OO 6.OO Monostearate MCT OIL NA NA NA 6.OO NA Cocoglycerides 2.OO NA NA NA NA Methy Glucose NA NA 3.00 NA NA Sesquistearate PEG 1 OO Stearate NA OSO NA NA NA (Myri 59) Hydrogenated 3.SO 3.SO 1...SO 3.SO NA Castor Oil Steareth-2 NA NA S.OO NA NA Steareth-20 NA NA 2.50 NA NA US 2010/031 0476 A1 Dec. 9, 2010 39

TABLE 2-continued Further Development of a foamable carrier for doxycycline hyclate and doxycycline monohydrate

Lot:

DOX-O22 DOX-O2S DOX-026 DOX-O27 DOX-033 % ww % Wiw % Wiw % Wiw % Wiw

Aluminum Starch 10.00 1O.OO 10.00 10.00 NA Octylsuccinate Diisopropyl adipate 8.00 8.OO 8.00 8.00 NA Doxycycline 1.17 NA 1.16 1.16 NA Hyclate Doxycycline NA 1.04 NA NA 1.04 Monohydrate

Control 100.00 100.00 100.00 100.00 100.00 Propellant 1681 12.00 12.00 12.00 12.00 12.00

Control II 112.00 112.OO 112.00 112.00 112.OO Date manufacture 18-June- 20-June- 31-July- O1-August- 12 2007 2007 2007 2007 September 2007 Foam quality G FG to G FG to G FG to G G Shakability 1 2 1 1 2 Expansion Not tested 97 Not tested Not tested Nottested Time(sec) Collapse Time >300 150 150 150 240 (Sec) Hardness (g) 24.59 10.92 Not tested Not tested 18.46 Viscosity (cPs) 6789 10710 1071.O not tested 1051 ORPM tested on PFF only Density (g/ml) O.193 O.O79 O419 O. 142 O.168 Assay at T-0 (% w/w)

O.77-PFF 0.82-PFF Not tested Not tested 0.92-PFF 0.96-foam 0.96-foam 0.94-foam Assay after 3 months of storage

50 C. 0.85-foam O.78 Not tested Not tested O.89 25o C. 0.87-foam O.70 Not tested Not tested O.88 30° C. 0.90-foam O.68 Not tested Not tested O.89 40° C. 0.82-foam O.61 Not tested Not tested O.87

NA—not applicable G—good FG-fairly good PFF-Pre foam formulation

0545. Addition of cocoglycerides to formulation DOX General Manufacturing Procedures for DOX Formulations: 022 may account for the improved foam quality compared to 0550. In order to prepare an agent free pharmaceutical DOX-025 formulation where surfactant PEG 100 Stearate composition and a pharmaceutical composition comprising was incorporated instead of cocoglycerides. an agent, the following steps were followed. 0546 Exclusion of cocoglycerides and incroporation of 0551 Preparation of a Pre-foam formulation (PFF) Steareth-2, Steareth-20 and methyl glucose sesquistearate to 0552 Milling of Doxycycline Hyclate/Monohydrate. DOX-026 did not result in an improvement in the foam qual The range of the particle size is minimum 2.2 Lum-maxi ity of the formulation. mum 41 um. 0547. The number of ingredients were significantly 0553. Addition of Doxycycline Hyclate/Monohydrate reduced in formulation DOX-033. This formulation revealed 0554 FormulationDOX-026 PFF preparation (see Table 3 good foam quality. for further process details) (0548. Formulation DOX-033 appears to be chemically 0555 Heat up the Light mineral oil to 70° C. Add Oleyl stable during 3 months of storage at different temperatures. alcohol, Octyldodecanol 0549 Complex formulations with a high array of ingredi 0556. Add Hydrogenated Castor Oil under mixing until ents (DOX-022, DOX-025, DOX-26 and DOX-027) were completely dissolution. Add Myristyl alcohol, Cetearyl found to be chemically unstable. Octanoate under mixing. US 2010/031 0476 A1 Dec. 9, 2010 40

0557. Add Glyceryl Monostearate, Stearyl alcohol, Ste areth-20, Steareth-2, Cyclomethicone and Methyl Glu TABLE 5 cose Sesquistearate under mixing. Ingredients for batch DOX-033 0558 Cool down to 60° C., add the PPG-15 Stearyl Supplier and Ether, Mix till the ingredients are completely dissolved. Name Brand name Address 0559. Add Diisopropyladipate under mixing. PPG-15 Stearyl Ether Sympatens ASP/150 Kolb 0560 Cool down to 40°C., add the Aluminum starch Octyldodecanol Eutanol GPH Cognis Light mineral oil Pioner 2076P Hansen & Octenylsuccinate under mixing until complete disper Rosenthal S1O. Cyclomethicone DOW Glyceryl monostearate Cltina GMSWPH Cognis 0561 Cool down to RT. Stearyl alcohol Speziol C18 PH Cognis 0562 Mill Doxycycline Hyclate by mortar. This proce Myristyl Alcohol Speziol C14 Cognis Doxycycline Monohydrate Doxycycline Monohydrate dure is performed according to MSDS of antibiotic. Propellant 1681 0563 Add the Doxycycline Hyclate, mix until homog enous Suspension.

TABLE 3

Production Procedure for DOX-026 Required Time Mixing rate Procedure (min) Temp (C.) (rpm) PFF (pre-foam formulation) Heating of Light Mineral Oil, Oleyl 2O 70 400-600 preparation alcohol, Octyldodecanol Addition of Hydrogenated Castor 10-15 70 400-600 Oil, Cetearyl Octanoate and Myristyl alcohol Addition of Glyceryl monostearate 10-15 70 400-600 Stearyl alcohol, Steareth 20, Steareth 2, Methyl Glucose Sesquistearate, Cyclomethicone Addition of PPG-15 Stearyl ether S-10 60 400-600 Addition of Di-isopropyl adipate and 15-20 70 400-600 Cooling down and add Aluminum 10-20 40 400-600 Starch Octenylsuccinate Addition of Milling of Doxycycline Hyclate by na rt. na Doxycycline mortar Hyclate Addition of Doxycycline Hyclate to S-10 rt. SSOO-6OOO the PFF

0564 One example of the canisters and closures used in Manufacturing Procedure for DOX-033 this disclosure are presented in Table 4. Step 1-a: Preparation of PFF TABLE 4 0566 Heat up the Light mineral oil to 70° C. AddOctyl dodecanol. Canister and Packaging of DOX-026 0567 Add Myristyl alcohol. Supplier, Supplier address and 0568 Add Glyceryl Monostearate and Stearyl alcohol Bottle kind closure system Product number under mixing. Pressurized Nussbaum monoblock Weiss unberdruck NG 35.07OFoamix 0569 Cool down to 60° C., add the PPG-15 Stearyl aluminum canisters 35 x 70mm, Nussbaum AG Ether, Cyclomethicone. Mix till the ingredients are com phenol-epoxy lacquer pletely dissolved. Valve OO64061, Seaquist, France 0570 Cool down to 30° C. Actutor 1010274 Seaquist, France Step 2: Addition of Doxycycline Monohydrate to Formula tion Experimental Procedure for Batch No. DOX-033 0571 Milled Doxycycline Monohydrate by mortar. 0565 Formulation DOX-033 contains minimal excipients This procedure is performed according to MSDS of composition and another salt of Doxycycline was used— antibiotic. Doxycycline Monohydrate. In addition, the propellant con 0572. Add the Doxycycline Monohydrate, mix until centration raised to 12% instead of 8% in previous formula homogenous Suspension. tions (see DOX-26 and 27). 0573 Cool down to RT. US 2010/031 0476 A1 Dec. 9, 2010 41

Production Procedure Record for DOX-033 0574)

TABLE 6

Process Details for batch DOX-033 Required Mixing rate Procedure Time (min) Temp (C.) (rpm) PFF (pre-foam formulation) Heating of Light Mineral 2O 70 400-600 preparation Oil & Octyldodecanol Addition Myristyl alcohol 10-15 70 400-600 Addition of Glyceryl 10-15 70 400-600 monostearate and Stearyl alcohol Addition of PPG-15 S-10 60 400-600 Stearyl ether, & Cyclomethicone Cooling down 10-20 40 400-600 Addition of Grinding of Doxycycline na RT na Doxycycline Monohydrate by mortar Monohydrate Addition of Doxycycline S-10 40- RT SSOO-6OOO Monohydrate to the PFF nia—not applicable RT room temperature

(0575 Formulation DOX-033 was filled in following pack Example 2 aging configurations: 0576 1. Nussbaum aluminum monoblock canisters, 30+5 g of PFF, crimped and pressurized with 12% propellant. Foamable Carriers for Minocycline 0577 2. Amber glass bottles filled with 20+5 g of PFF under nitrogen environment and without nitrogen. 0578. 3. Canisters were stored in upright or inverted posi 0581. A series of experiments was performed to find suit tions for 3 weeks. able formulations of foamable carriers for minocycline. Simi 0579. Without wishing to be bound to any theory, the lar steps were taken to those described with respect to Table 1, formulations produced appeared to be suspensions of Solid including: surfactants in an oily phase. Of all the formulations 0580 DOX-001-033, DOX-033 was found to be the most 0582 other additives to improve foam quality stable. The concentration of doxycycline was monitored over 0583 change of surfactants and polymers to improve foam time. There was originally 1.04 g of doxycycline in the com quality position. Table 7 shows the concentration measured as a func 0584) use of unstable agent compatible materials perTable tion of time and storage conditions: 19

TABLE 7 Concentration of doxycycline monohydrate in DOX-033 formulation measured over time at different storage temperatures. Foam Assay 5oC. 25o C. 30° C. 40° C. (% w/w) Specifications Up inv Up inv up inv up inv

TO Labeled O.93 0.93 0.93 0.93 O.93 0.93 0.93 0.93 conc.-1.0% Range: 0.90-1.10 (90.0-110.0%) 3 weeks labeled conc.- O.89 O.88 O.88 O.88 O.89 O.88 (O.86 0.86 storage 1.0% Range: 0.90-1.10 (90.0-110.0%) Up = upright position Inv = inverted position US 2010/031 0476 A1 Dec. 9, 2010 42

Some of the results appear in Tables 8-11 hereinbelow. 0593 PFF was packed in Nussbaum aluminum monob lock canisters and Plastic-coated, pressurizable glass aerosol TABLE 8 container (LM Wheaton, M-937F, supplied as GK-500 by Development of a foamable carrier for minocycline Aero-Tech Laboratory Equipment Lot: TABLE 9 MCH-OO1 MCH-022 Development of a foamable carrier for minocycline % Wiw % Wiw Composition MCH-087-(Placebo) MCH-087-071021 Titanium Dioxide 2.OO CyclomethiconeCyclomethicone 3.00 PPG-15 Stearyl 1S.OO 1S.OO (DC 345 fluid) Ether PPG-15 Stearyl Ether 1S.OO 1S.OO Octyldodecanol 12.00 12.00 Octyldodecanol 12.00 12.00 Light mineral oil 50.50 48.99 Light mineral oil 31.93 17.93 Polyacrylamide/Isoparaffin? S.OO S.OO Oleyl alcohol 10.00 1O.OO Laureth-4 (Sepigel 305) Glycerol monostearate 4.OO 4.OO Cyclomethicone 3.00 3.00 Diisopropyl adipate 8.00 8.OO Glyceryl 6.OO 6.OO Stearyl alcohol 4.OO 4.OO nonOStearate Myristyl alcohol f 1.OO Stearyl alcohol 6.OO 6.OO Hydrogenated Castor Oil f 1...SO Myristyl alcohol 2.50 2.50 Cetearyl Octanoate/Sucrose 1...SO 2.OO Minocycline NA 1.26 distearate Hydrochloride Polyoxyl 20 Stearyl Ether 2.50 2.50 Polyoxyl 2 Stearyl Ether S.OO S.OO Control: 1OOOO 100.00 Aluminum Starch S.OO 1O.OO Propellant 1681 12.00 12.00 Octenylsuccinate Homogeneity test separation <5% homogenous, Metyl Glucose Sesquistearate f 3.00 at pressurized glass spillable viscous Minocycline HCL 1.07 1.07 aerosol container after 1 day spillable storage at 25°C. Control 98.93 1OOOO Homogeneity test separation <5% homogenous, Propellant 12.00 12.00 at pressurized glass spillable viscous aerosol containers after 1 spillable, shakable: Control II 112.00 112.OO month storage at 25°C. Results Viscosity (cPs) 847.82 1045.75 Foam quality FG G Foam quality G G Viscosity (cPs) 10 RPM 84.4 4787 Shakability 2 2 Density N.A O.136 Shakability Good Good NA—not applicable G—good foam quality FG-Fairly good foam quality G—good quality 0594. Manufacturing Procedure for MCH-087 0585. The effect of selected factors on the formulation of 0595 Step 1-a: Preparation of Light Mineral Oil Mixture a 1% Minocycline HCl foam product and its properties were 0596 Heat up the Light mineral oil to 70-75° C. Add evaluated. Octyldodecanol. 0586 1. Cyclomethicone: to impart a non-greasy skin 0597 Add Myristyl alcohol with mixing. feeling. 0598. Add Glyceryl Monostearate and Stearyl alcohol 0587 2. Titanium dioxide: to give a lighter foam color and under mixing. to impart a sunscreen effect (MCH causes yellow discol 0599 Step 1-b: Premix of Sepigel 305 in Cyclomethicone oration of the skin and increased photosensitivity). 0600 Heat the cyclomethicone to 70-75° C. Introduce 0588 3. Different proportions of oils as listed below. slowly by portions the Sepigel 305 at 75° C. with mix Formulation MCH-022 is one of the rational design matrix ing. array. 0601 Step 1-c: Incorporation of Sepigel 305 into the Oil 0589 Formulations were prepared by heating the oils anto Mixture 65-70° C. following by addition of surfactants/adjuvant. 0602 Incorporate slowly the Step 1-b product into the Minocycline HCl was incorporated at 30°C. Step 1-a mixture at 75° C. at least. 0590 Minocycline HCl is a solid and is presented as a 0603 Step 1-d. Addition of PPG-15 Stearyl Ether solid suspension in the formulations therefore preferably one 0604 Cool down the mixture from Step 1-a to 60° C., or more agents, which can be added that are capable of pro add the PPG-15 Stearyl Ether. Mix till the ingredients viding a uniform Suspension should be identified. are completely dissolved. 0591. The effect of Sepigel 305 (polyacrylamidefisopar affin/Laureth-7) was examined in formulation MCH-087 0605 Cool down to 30° C. with and without API. 0606 Add Minocycline HCl by continuous mixing. 0592. Addition of Minocycline HCl at concentration of Formulation was filled in Nussbaum aluminum monoblock 1.18% w/w changes the physical and chemical properties of canisters, 30+5 g of PFF, crimped and pressurized with 12% formulation. propellant. US 2010/031 0476 A1 Dec. 9, 2010 43

0610 General properties of minocycline HCl: TABLE 10 0611 1. Slightly hygroscopic, yellow crystalline odorless powder with a slight bitter taste. Chemical Stability of MCH-087 formulation stored in canisters at upright and inverted positions after three weeks storage at 25°C. 0612. 2. Relatively stable as a solid powder, however, and 40°C. undergoes degradation in aqueous solutions. 0613. 3. The major degradative pathways are carbon-4 TO 3 weeks 3 weeks epimerization and oxidative processes. Since the oxidized products are frequently dark in color, objectionable color PFF (pre-foam stability 25 C. stability 40 C. changes are often encountered before the loss of activity formulation Foam Up inv up inv becomes appreciable. Epimerization continues until equi librium between minocycline and its epimer is achieved. Assay (% w/w) 1.2O 1.08 1.17 1.15 1.09 1.03 of labeled 0.614. It is known from the literature that oxidation of conc-1.0% + tetracycline antibiotics can occur at any pH. O.1 0615. The compatibility tests were made of a selection of Up = upright a wide range of different types of excipients as can be seen in Inv = inverted Table 12 below. For convenience the excipients were divided into four different groups (I-IV). Formulation was stable following the storage at 40°C. for 3 0616. Different compositions of hydrophilic and hydro weeks. phobic solvents containing minocycline HCl were prepared 0607 Formulations MCH-075 and MCH-076 contain by weighing the antibiotic in a glass vial and shaking over minimal excipients in compositions. Corn starch derivative night with each solvent investigated (Group I and II). aluminum free (Dry-Flo R AF) was added to formulation 0617. Mixtures of Minocycline HCl with solid excipients MCH-105 to reduce the tackiness. Formulation MCH-109 like titanium dioxide, Stearyl alcohol, myristyl alcohol etc contains Octyldodecanol instead of PPG-15 Stearyl Ether but were prepared by suspending Minocycline HCl in oil with did not achieve any reasonable foam quality such as MCH stirring and then adding the Solid ingredient as a powder with O75. stirring at room temperature (Group III an IV).

TABLE 11 Development of additional foamable carrier for minocycline Composition MCH-072 MCH-075 MCH-076 MCH-105 MCH-107 PPG-15 Stearyl 1S.OO 42.21 42.21 1S.OO Ether Octyldodecanol 12.00 NA NA 12.00 12.00 Light mineral oil 54.32 42.21 42.21 49.83 49.33 Polyacrylamide/Isoparaffin? NA NA NA S.OO 3.00 Laureth-4 (Sepigel 305) Cyclomethicone 3.00 NA NA 3.00 3.00 Glyceryl 6.OO 6.OO 6.OO 6.OO 6.OO nonOStearate Stearyl alcohol 6.OO 6.OO 6.OO NA NA Myristyl alcohol 2.50 NA NA NA 2.50 Cocoglycerides NA 2.50 NA NA NA Corn starch NA NA NA 8.00 8.OO derivative (Dry-Flo (RAF) Minocycline 1.18 1.18 1.18 1.18 1.18 Hydrochloride

Control: 1OOOO 100.00 1OOOO 100.00 1OOOO Propellant 1681 12.00 12.00 12.00 12.00 12.00 Foam quality Good Good Good Good Good Shakability 2 2 2 2 NA—not applicable

0608 Comment: Formulation MCH-75 was repeated 0618. Oxidation of minocycline after the storage at vari using Octyldodecanol instead of PPG-15 Stearyl Ether but ous temperatures was detected by color change. Assay for did not achieve a reasonable foam quality content of the active pharmaceutical ingredient (API) and Example 3 degradation product (4-epiminocycline) was determined in Examples of Compatibility Testing Some samples. Part A Minocycline 0619. The major degradative pathways for Minocycline 0609. The physicochemical properties of minocycline are carbon-4 epimerization and oxidative processes. Minocy HCl are similar to those of other tetracycline antibiotics with cline is relatively stable as a solid powder, however, it under the exception of differences resulting from the presence of a goes degradation in aqueous solutions. Many different second dimethylamino group. excipients cause the Minocycline oxidation (see the incom US 2010/031 0476 A1 Dec. 9, 2010 44 patibility tables 13a, 13b, 13c and 13d herein). Epimerization morning. Clear Supernatant was collected in a separate vessel continues until equilibrium between minocycline and its and stored in a dessicator. epimer is achieved. 0623 The following were tested using the above proce 0620 Since the oxidized products are frequently dark in dure. mixtures of Minocycline with PEG 200, PEG 400, color, objectionable color changes are often encountered glycerol, prolylene glycol, polyethylene glycol. It was before the loss of activity becomes appreciable. The analyti observed that Minocycline HCL oxidized quickly after dis cal method doesn't detect the “oxidative Minocycline. It solution in all the different “dryed hydrophilic vehicles should be noted that an oxidized product is evident by color ("dryed by the Magnesium Sulfate procedure) that were change. It is not necessary to detect it chromatographically, tested. It was concluded that pre drying the excipients did not but a low Minocycline assay result can be seen compared to help to prevent rapid breakdown and therefore the cause must the Zero time value (T-0) when this process happens inside be some other reason. the canister. At higher temperatures (30°C., 40°C., 50° C.) 0624. A series of experiments were performed to evaluate the oxidation process is even more noticeable. Epimerization which mixture of components/ingredients were compatible levels are around 2-5% of API assay. or incompatible with minocycline. Each component or com 0621. Without being bound to any theory, it seems that binations of components were mixed with either 1.1% or water residues in hydrophilic vehicles like propylene glycol, 2.2% Minocycline HC1. The glass vials containing the for polyethylene glycol 200 and 400 (PEG 200 and PEG 400 mulations were wrapped in aluminum-and were Subjected respectively) and glycerol are responsible for fast oxidation to a range of temperatures 25°C.; 30° C.; 40° C.; 50C; for and epimerization of Minocycline. between one week to about 3 weeks. The results of these 0622. A special procedure for drying of water residues was experiments are shown in Table 13a to 13e. The best results developed. Magnesium Sulphate was added to the glass bea are shown as “compatible no oxidation'. The results indicate ker filled with one of the hydrophilic vehicles. The mixture that these components on their own can be used in formula was stirred during overnight and centrifuged the following tions with minocycline.

TABLE 1.3a

Results of Group I Compatibility tests

Mixtures with 2.2% of Minocycline HCl stored for 10 days at 50° C. Ingredients

PPG-15 stearyl Mineral Propylene Diisopropyl Group I Cyclomethicone ether Octyldodecanol oil glycol Glycerol PEG 200 PEG 400 MCT oil adipate

Visual bright yellow bright bright yellow bright dark Orange Orange Orange bright bright yellow inspection mixture yellow mixture yellow brown brown brown brown yellow solution mixture mixture Solution solution Solution solution mixture Compatibility compat. compat. compat. compat. Oil Oil Oil Oil compat. compat Results no oxidation O no oxidation O compat... compat. compat. compat. O no oxidation oxidation oxidation Oxidation oxidation oxidation oxidation oxidation

Notes and abbreviations: compat, = compatibility;

TABLE 13b Results of Group I Compatibility tests Mixtures with 2.2% of Minocycline HCl stored for 10 days at 50° C. Ingredients

Sorbitan Dimethyl Group I Cetearyl octanoate Hexylene glycol Butylene glycol Monolaurate Isosorbide Visual bright yellow bright orange brown orange brownish orange brownish yellow inspection mixture mixture Solution mixture mixture Compatibility compat. Non compat. Non compat. Non compat. Non compat. Results no oxidation oxidation oxidation oxidation oxidation US 2010/031 0476 A1 Dec. 9, 2010 45

TABLE 13c Results of Group II Compatibility tests Mixtures with 1.1% of Minocycline HCl after 10 days storage at 40°C. Ingredients Propylene Ethanol 95% glycol PEG 200 Ethanol with BHT with ascorbic with ascorbic Time 95% and Ascorbic acid acid Group II points Ethanol 95% with BHT acid and Vit E and Vit E Isostearic Acid Minocycline TO 0.97 0.97 O.91 O.81 O.74 NP Assay (% w/w) 10 days at O.S2 O.S2 O.O7 O.13 O.22 40° C. 4-epiminocycline T-0 O.O21 O.O21 O48 O.47 0.44 NP Assay (% w/w) 10 days at O.39 O.39 O4O O.38 O.36 40° C. Visual inspection 10 days at Bright orange Bright orange Bright orange Bright orange Bright orange Orange 40° C. solution Solution Solution. Solution Solution solution Compatibility Non Non Non Non compatible Non compatible Non compatible Results compatible compatible compatible Oxidation Oxidation Oxidation Oxidation Oxidation Oxidation BHT-butylated hydroxytolyene; WitF—vitamin E

TABLE 1.3d Results of Group III Compatibility tests Group III Assay (% WW) of Minocycline and 4-epininocycline following three weeks storage Mixture composition TO 25o C. 30° C. 40° C. PPG-15 SE: Octyldodec; Minocycline O.9S O.95 O.93 O.94 Mineral oil 4-Epiminocycline O.018 O.O16 O.O14 O.O23 Visual inspection yellow mixture yellow mixture yellow mixture yellow mix Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation PPG-15 SE: Octyldodec; Minocycline O.9S O.90 0.97 O.82 Mineral oil + oleyl alcohol 4-Epiminocycline O.O2O O.O21 O.O15 O.O23 Visual inspection yellow mixture yellow mixture yellow mixture yellow mix Compatibility compatible compatible compatible Reduction of assay Results no oxidation no oxidation no oxidation PPG-15 SE: Octyldodec; Minocycline O.93 O.86 O.99 O.64 Mineral oil + oleyl 4-Epiminocycline O.048 O.045 O.O40 O.O37 alcohol + Brij 20 and Brij 2 Visual inspection yellow mixture brownish orange brownish orange Brown mixture mixture mixture Compatibility compatible non compatible non compatible non compatible Results no oxidation oxidation oxidation oxidation PPG-15 SE; Minocycline 1.06 O.99 1.02 1.01 Mineral oil + ASOS 4-Epiminocycline O.O1 <0.01 <0.01 <0.01 Visual inspection bright yellow bright yellow bright yellow bright yellow mixture mixture mixture mixture Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation PPG-15 SE: Octyldodec; Minocycline O.90 O.80 O.80 0.55 MGSS 4-Epiminocycline O. 120 O.121 O.O6 O.08O Visual inspection yellowish orange brownish orange Brown mixture Black mixture mixture mixture Compatibility non compatible non compatible non compatible non compatible Results oxidation oxidation oxidation oxidation PPG-15 SE: Octyldodec; Minocycline O.94 1.02 0.97 O.98 DISPA 4-Epiminocycline O.O26 O.O34 O.O12 O.O17 Visual inspection bright yellow bright yellow bright yellow bright yellow mixture mixture mixture mixture Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation PPG-15 SE: Octyldodec; Minocycline O.83 O.80 O.80 0.79 cetearyl octanoate 4-Epiminocycline O.O28 O.O14 O.O12 O.018 Visual inspection bright yellow bright yellow bright yellow bright yellow mixture mixture mixture mixture Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation US 2010/031 0476 A1 Dec. 9, 2010 46

TABLE 13d-continued Results of Group III Compatibility tests Group III Assay (% WW) of Minocycline and 4-epininocycline following three weeks storage Mixture composition TO 25o C. 30° C. 40° C. PPG-15 SE: Octyldodec; Minocycline O.98 O.90 O.92 O.92 cyclomethicone 4-Epiminocycline O.O3O O.O34 O.O15 O.O34 Visual inspection bright yellow bright yellow bright yellow bright yellow mixture mixture mixture mixture Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation Light mineral oil; Minocycline O.9S O.96 O3 1.07 Hydrog. castor 4-Epiminocycline O.O31 O.O36 O.O15 O.O33 oil + Stearyl/myristyl alcohol Visual inspection bright yellow bright yellow bright yellow bright yellow mixture mixture mixture mixture Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation Light mineral oil; Minocycline 0.97 O.99 O7 1.16 titanium dioxide 4-Epiminocycline O.O31 O.O16 O.O17 O.O22 Visual inspection bright yellow bright yellow bright yellow bright yellow mixture mixture mixture mixture Compatibility compatible compatible compatible compatible Results no oxidation no oxidation no oxidation no oxidation

Notes and abbreviations: PPG-15SE. Polypropylene Glycol Stearyl Ether Octyldodec.—octyldodecanol ASOS–Aluminum Starch Octenylsuccinate MGSS-Methyl Glucose Sesquistearate DISPA-Diisopropyl adipate Hydrog, castor oil—Hydrogenated castor oil Mixture- the light yellow liquid supernant with powdered sediment of antibiotic

TABLE 13e TABLE 13e-continued Results of Group IV Compatibility tests Results of Group IV Compatibility tests Assay (% w/w) of Minocycline Assay (% w/w) of Minocycline and 4-epiminocycline and 4-epiminocycline Group IV Mixture following one week storage Group IV Mixture following One week storage composition 25o C. 40° C. composition 25o C. 40° C. PPG-15 SE; Minocycline O.87 PPG-15 SE; Minocycline O.98 O.92 Octyldodec; Octyldodec; Cocoglucoside + 4-Epiminocycline Not performed O.10 PEG 40 Stearate 4-Epiminocycline O.04 O.04 Coconut alcohol Visual inspection Yellow mixture Yellow mixture Visual inspection Yellow mixture Yellow mixture Compatibility compatible compatible Compatibility compatible compatible Results no oxidation no oxidation Results no oxidation no oxidation PPG-15 SE; Minocycline 1.04 1.02 Octyldodec; Abbreviations: PEG 100 Stearate 4-Epiminocycline O.O3 O.O3 PPG-15 SE. Polypropylene Glycol Stearyl Ether Visual inspection Yellow mixture Yellow mixture Octyldodec.—octyldodecanol Compatibility compatible compatible Results no oxidation no oxidation 0625. It should be understood that the results displayed in PPG-15 SE; Minocycline O.96 1.10 Table 13a to 13e provide for a new methodology in defining Octyldodec; Sorbitan 4-Epiminocycline O.08 O.12 the compatibility between unstable active agents and one or Monostearate more components in a composition or formulation. Not only Visual inspection Yellow mixture Yellow mixture are these results applicable for preparing pharmaceutical Compatibility compatible compatible compositions with unstable active agents, which is a very Results no oxidation no oxidation useful embodiment of the present disclosure, but this meth PPG-15 SE; Minocycline O.91 1.01 Octyldodec; odology also provides new information regarding the combi Cocoglycerides 4-Epiminocycline O.O1 O.O2 nation of different components/ingredients in the preparation Visual inspection Yellow mixture Yellow mixture of carriers, compositions and formulations perse (excluding Compatibility compatible compatible an active ingredient). Thus, the results of Table 20 provide for no oxidation no oxidation definition of “unstable active agent-compatible (UAAC) components or ingredients, which may be advantageously US 2010/031 0476 A1 Dec. 9, 2010 47 used in the preparation of stable compositions. Thus, 0631 3. Doxycycline hyclate has a high degree of lipid “unstable active agent-compatible (UAAC) components solubility and a low affinity for calcium binding. tend to be useful in the preparation of stable formulations with/without an active agent. Doxycycline Monohydrate Part B Doxycycline 0632 1. Doxycycline is a broad-spectrum antibiotic syn 0626. A similar compatibility study was conducted for thetically derived from oxytetracycline. Doxycycline Hyclate and Doxycycline Monohydrate. 0633 2. The chemical designation of the light-yellow 0627 The physicochemical properties of these two forms crystalline powder is alpha-6-deoxy-5-oxytetracycline. of Doxycycline are similar to those of other tetracycline anti 0634. The major degradative pathways for both types of biotics with the exception of differences resulting from prima Doxycycline are carbon-4 epimerization and oxidative pro facie the presence of a HO molecule in Doxycycline Mono CCSSCS. hydrate and a HO molecule and two HCl molecules for every 0635 Doxycycline is a member of the tetracycline antibi water molecule in Doxycycline Hyclate. otics group and is commonly used to treat a variety of infec 0628 General properties of Doxycycline Hyclate and tions, particularly effective in treating acne condition. Doxycycline Monohydrate: 0636. Different compositions of hydrophilic and hydro phobic solvents containing Doxycycline Hyclate (Set I and Doxycycline Hyclate Set II) and Doxycycline Monohydrate (Set III) were prepared 0629. 1. Doxycycline Hyclate is a broad-spectrum antibi by weighing the antibiotic in a glass vial and shaking over otic synthetically derived from oxytetracycline. night with each solvent investigated. Mixtures of Doxycy 0630 2. Doxycycline hyclate is a yellow crystalline pow cline salts 1.04% w/w with solid excipients were prepared in der soluble in water and in solutions of alkali hydroxides a similar way as for Minocycline HC1. The results are pre and carbonates. sented in Tables 14a to 17.

TABLE 14a

Doxycycline Hyclate Compatibility Test (Group I)

Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25°C., 40° C. and 50° C. for two weeks Ingredients

PPG-15 stearyl Mineral Propylene Diisopropyl Group I Cyclomethicone ether Octyldodecanol oil glycol Glycerol PEG 200 PEG 400 MCT oil adipate

Visual White White White White Light Light Light Light White White inspection iquid and iquid and liquid and iquid and yellow yellow yellow yellow iquid and liquid and at T-O yellow yellow yellow yellow Solution solution Solution solution yellow yellow powder powder powder powder powder powder sedim. sedim. sedim. sedim. sedim. sedim. Visua White White White White Light Light Light Light White White inspection iquid and iquid and liquid and iquid and yellow yellow yellow yellow iquid and liquid and after the yellow yellow yellow yellow Solution solution Solution solution yellow yellow storage at powder powder powder powder powder powder 25o C. sedim. sedim. sedim. sedim. sedim. sedim. Visua White White Light White Yellow brownish Brown Orange White White inspection iquid and iquid and orange iquid and solution Yellow Solution solution iquid and liquid and after the yellow yellow Solution yellow solution yellow yellow storage at powder powder powder powder powder 40° C. sedim. sedim. sedim. sedim. sedim. Visua White White Orange White Brownish Light Orange Orange White White inspection iquid and iquid and solution iquid and Orange brown Solution solution iquid and liquid and after the yellow yellow yellow Solution solution yellow yellow storage at powder powder powder powder powder 50° C. sedim. sedim. sedim. sedim. sedim. Compatibility Compat. Compat. Non Compat. Non Non Non Non Compat. Compat Results O O compat. O compat.. compat. compat. compat. O O after the oxidation oxidation no oxidation oxidation oxidation oxidation oxidation oxidation oxidation storage oxidation US 2010/031 0476 A1 Dec. 9, 2010 48

TABLE 1.4b. Doxycycline Hyclate Compatibility Test (Group I) (continued Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25°C., 40° C. and 50° C. for two weeks Ingredients

Sorbitan Group I Cetearyl octanoate Hexylene glycol Butylene glycol Monolaurate Dimethyl Isosorbide Visual inspection at T-O bright yellow bright yellow bright yellow bright yellow yellow solution solution Solution Solution mixture Visual inspection after bright yellow bright yellow bright yellow Brown solution Yellow solution the storage at 25°C. solution Solution Solution Visual inspection after bright yellow light yellow solution Light orange Brown solution Brownish orange the storage at 40°C. solution Solution Visual inspection after White liquid and Light yellow liquid Light orange Black Solution Orange solution the storage at 50° C. yellow powder and yellow powder Solution sedim. sedim. Compatibility Compat. Compat. Non compat. Non compat. Non compat. Results no oxidation no oxidation oxidation oxidation Oxidation

Group II included Doxycycline Hyclate mixed with various vehicles with addition of antioxidants like alpha tocopherol, butylated hydroxytolyene (BHT), ascorbic acid.

TABLE 1.5 Doxycycline Hyclate Compatibility Test (Group II Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25°C., 40° C. and 50° C. for two weeks Ingredients Propylene glycol, PEG 200, alpha Ethanol 95%, BHT and alpha tocopherol and tocopherol and Group II Ethanol 95% Ethanol 95% and BHT and ascorbic acid ascorbic acid ascorbic acid Visual inspection bright yellow bright yellow bright yellow bright yellow bright yellow at TO Solution Solution Solution Solution Solution Visual inspection bright yellow bright yellow Yellow solution bright yellow Yellow solution after the storage at Solution Solution Solution 25o C. Visual inspection bright yellow bright yellow Yellow solution Light orange solution Orange solution after the storage at Solution Solution 40° C. Visual inspection bright yellow bright yellow Orange solution Light orange solution Brownish orange after the storage at Solution Solution Solution 50° C. Compatibility compatible. compatible Non compatible. Non compatible. non compatible. Results no oxidation no oxidation oxidation oxidation Oxidation

TABLE 16 Doxycycline Hyclate Compatibility Test (Group III Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25°C., 40° C. and 50° C. for 3 days Ingredients Steareth Hydrogenated Myristyl alcohol Isostearic Oleyl 20 and Castor and PEG 40 PEG 100 Sorbitan Group II Acid alcohol Steareth 2 Oil Stearyl alcohol Stearate Stearate MonoStearate Cocoglycerides Visual Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow inspection Suspen Suspen Suspen Suspen Suspen Suspen Suspen Suspen Suspen at TO Visual Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow inspection after Suspen Suspen Suspen Suspen Suspen Suspen. Suspen Suspen Suspen the storage at 25o C. US 2010/031 0476 A1 Dec. 9, 2010 49

TABLE 16-continued Doxycycline Hyclate Compatibility Test (Group III)

Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25°C., 40° C. and 50° C. for 3 days ngredients

Steareth Hydrogenated Myristyl alcohol Isostearic Oleyl 20 and Castor 8 PEG 40 PEG 100 Sorbitan Group II Acid alcohol Steareth 2 Oil Stearyl alcohol Stearate Stearate MonoStearate Cocoglycerides

Visual Yellow Yellow Brown Yellow Yellow Brown Yellow Yellow Yellow inspection after Suspen Suspen Suspen Suspen SUSel Suspen Suspen Suspen Suspen the storage at 40° C. Visual Yellow Yellow Brown Yellow Yellow Brown Yellow Yellow Light inspection after Suspen Suspen Suspen Suspen SUSel Suspen Suspen Suspen brown the storage powder at SO C. Compatibility Compat. Compat. Non Compat. Compat. Non Compat. Compat. Non Results O No compat. No No Compat. No No Compat. oxidation oxidation Oxidation oxidation oxidation oxidation oxidation oxidation oxidation suspen.—suspension; Compat—compatible

A similar compatibility test was performed on another form of Doxycycline-Doxycycline Monohydrate. The results are presented in Table 17a. Table 17b and Table 18.

TABLE 17a Doxycycline Monohydrate Compatibility Test (Group I) Mixtures of 1.04% w/w of Doxycycline Monohydrate stored at 25°C., 40°C., and 50° C. for two weeks Ingredients

PPG-15 stearyl Mineral Propylene Diisopropyl Group I Cyclomethicone ether Octyldodecanol oil glycol Glycerol PEG 200 PEG 400 adipate

Visual White White White White Light yellow yellow Dark inspection iquid and liquid and liquid and iquid and yellow Solution solution yellow at TO yellow yellow yellow yellow solution Solution powder powder powder powder sedim. sedim. sedim. sedim. Visua White White White White Orange yellow Yellowish Yellowish inspection iquid and liquid and liquid and iquid and solution Solution black brown 8t le yellow yellow yellow yellow solution Solution storage at powder powder powder powder 25o C. sedim. sedim. sedim. sedim. Visua White Yellowish Orange White Black black Black Brown inspection iquid and Orange Solution iquid and solution Solution solution Solution 8tle yellow mixture yellow storage at powder powder 40° C. sedim. sedim. Visua White Yellowish Orange White black black Black Black inspection iquid and Orange Solution iquid and solution Solution solution Solution 8tle yellow mixture yellow storage at powder powder 50° C. sedim. sedim. Compatibility Compat. Non Non Compat. Non Non Non Non Non Non Results O compat. compat. O compat. compat. compat. compat. compat. compat. oxidation oxidation oxidation oxidation oxidation oxidation oxidation oxidation oxidation oxidation Storage US 2010/031 0476 A1 Dec 9, 2010 50

TABLE 17b Doxycycline Monohydrate Compatibility Test (Group I) (continued Mixtures of 1.04% w/w of Doxycycline Monohydrate stored at 25°C., 40°C., and 50° C. for two weeks Ingredients Group I Cetearyl octanoate Hexylene glycol Butylene glycol Sorbitan Monolaurate Dimethyl Isosorbide Visua White liquid and yellow White liquid and White liquid and yellow Brown mixture yellow solution inspection powder sedim. yellow powder powder sedim. at TO sedim. Visua White liquid and yellow bright yellow Orange solution orange solution orange solution inspection powder sedim. Solution after the storage at 25o C. Visua White liquid and yellow Brownish black Brownish black Brown solution Orange Orange inspection powder sedim. Solution Solution after the storage at 40° C. Visua White liquid and yellow Black Solution. black Solution brown solution Orange solution inspection powder sedim. after the storage at 50° C. Compatibility compat. Non compat. Non compat. Non compat. non compat. Results no oxidation oxidation oxidation oxidation Oxidation

TABLE 18 Doxycycline Monohydrate Compatibility Test (Group II Mixtures of 1.04% w/w of Doxycycline Monohydrate stored at 25°C., 40°C., and 50° C. for two weeks Ingredients Propylene glycol, PEG 200, alpha Ethanol 95%, BHT and alpha tocopherol and tocopherol and Group II Ethanol 95% Eathnol 95% and BHT and ascorbic acid ascorbic acid ascorbic acid Visual inspection bright yellow bright yellow bright yellow bright yellow bright yellow at TO Solution Solution Solution Solution Solution Visual inspection Brown solution Brown solution orange solution Yellowish orange Yellow solution after the storage at Solution 25o C. Visual inspection Brown solution Brown solution Orange solution Orange solution Dark yellow solution after the storage at 40° C. Visual inspection Black solution Black solution Black solution Brownish orange Brown orange after the storage at Solution Solution 50° C. Compatibility Non compatible. Non compatible Non compatible. Non compatible. non compatible. Results oxidation oxidation oxidation oxidation Oxidation

0637 Interesting and unexpected phenomena were found 0640. 3. Doxycycline Hyclate was stable in mixture with during the compatibility studies of Minocycline HCl, Doxy ethanol 95% and hexylene glycol. Doxycycline Monohy cycline Hyclate and Doxycycline Monohydrate: drate oxidized in the similar mixtures. 0638 1. Whilst Minocycline displayed intensive oxida 0641. 4. Unexpectedly addition of strong antioxidants like alpha-tocopherol and ascorbic acid did not prevent the tion on dissolution in glycerol. Surprisingly, the antibiotic oxidation of any of Minocycline HCL, Doxycycline revealed full compatibility with octyldodecanol, a Hyclate and Monohydrate in a waterless medium of pro branched chain fatty alcohol. Both molecules have the pylene glycol and PEG 200. similar hydroxyl units in their structures. 0642 5. Surprisingly, Doxycycline Hyclate revealed sta 0639 2. Doxycycline Hyclate and Monohydrate unex bility in Ethanol 95% following the storage at 40°C. and pectedly revealed different compatibility with excipients. 50° C. for two weeks although Minocyline HCl and Doxy For example, Doxycycline Hyclate was stable in mixture cycline Monohydrate changed their colour from yellow to with PPG-15 Stearyl Ether. Surprisingly, the Doxycycline orange upon dissolution in Ethanol 95%. Monohydrate was found to be non compatible with PPG 0643 6. In conclusion the following non predictable sub 15 Stearyl Ether during the storage at 40° and 50° C. for stance were found to be compatible with Minocycline and two weeks. Doxycycline: US 2010/031 0476 A1 Dec. 9, 2010

TABLE 19 Summary of MCH and DOX compatibility studies Compatibility tested after the storage for up to 3 weeks Minocycline Doxycycline Doxycycline Ingredient HCL Hyclate Monohydrate Comments Cyclomethicone 5 NF Yes Yes Yes All compatible PPG-15 Stearyl Ether Yes Yes No Octyldodecanol Yes No No Mineral Oil Yes Yes Yes All compatible Propylene Glycol No No No Glycerol No No No PEG 200 No No No PEG 400 No No No MCT Oil Yes Yes No Diisopropyl adipate Yes Yes No Ethanol 95% No Yes No Isostearic acid No Yes Not teste Oleyl alcohol Yes Yes Not teste Steareth 20 (Polyoxyl 20 No No Not teste Stearyl Ether) Steareth 2 (Polyoxyl 2 No No Not teste Stearyl Ether) Methylglycose No Not tested Not teste sesquistearate (MGSS) Aluminum Starch Yes Not tested Not teste Octenylsuccinate (ASOS) Cetearyl octanoate Yes Yes Yes All compatible Hydrogenated Castor Oil Yes Yes Not teste Stearyl alcohol Yes Yes Not teste Myristyl alcoho Yes Yes Not teste Titanium Dioxide Yes Not tested Not teste PEG 40 Stearate Yes No Not teste PEG 1 OO Stearate Yes Yes Not teste Sorbitan Monostearate Yes Yes Not teste Cocoglycerides Yes No Not teste Coconut Alcohol yes Not tested Not teste Hexylene glyco No Yes No Butylene glycol No No No Sorbitan Monolaurate No No No Dimethyl Isosorbide No No No Titanium dioxide Yes Not tested Not teste Methylglycose No Not tested Not teste sesquistearate (MGSS) Aluminum Starch Yes Not tested Not teste Octenylsuccinate (ASOS) Coconut alcohol Yes Not tested Not teste

0644 7. As could be seen from the Table 19 not all the Example 4 compatible with MCH ingredients are compatible with Doxycycline Hyclate or Monohydrate. For example, octyl Various Comparative Examples of Doxycycline and dodecanol is compatible with Minocycline HCl but Minocycline Formulations revealed incompatibility with Doxycycline Hyclate and 0646. The formulation of MCH072 is described in Table Monohydrate. Surprisingly, there are discrepancies in list 20 below. Table 21 describes compositions that failed to pro of ingredients compatible with Doxycycline Hyclate and vide foam of any quality. Doxycycline Monohydrate: for example PPG-15 Stearyl Ether is compatible with Doxycycline Hyclate and non TABLE 20 compatible with Doxycycline Monohydrate. 0645 8. The data presented herein could be used for selec Formulation of MCHO72 stock solution tion of active materials from tetracycline family for topical MCHO72--Stock formulations. A list of ingredients that were found to be solution compatible with MCH and DOX could be applied to other chemical name antibiotics from the tetracycline family. The following PPG-15 Stearyl Ether 1S.OO ingredients are suitable for topical formulations: mineral Octyldodecanol 12.00 oil, cyclomethicone, cetearyl octanoate. Few ingredients Light mineral oil 55.50 are compatible with both forms of doxycycline and are also Cyclomethicone 3.00 compatible with minocycline. US 2010/031 0476 A1 Dec. 9, 2010 52

TABLE 20-continued TABLE 21-continued Formulation of MCHO72 stock solution Comparative compositions that do not provide foam of any quality

MCHO72--Stock EXA2 EXA3 EXA2 Solution pressurized Pressurized pressurized with with with Glyceryl monostearate 6.OO Hydrocarbon hydrocarbon fluorocarbon Stearyl alcohol 6.OO Myristyl alcohol 2.50 Hydrogenated Castor Oil O.SO OSO Zinc Oxide 40.00 40.OO Control: 100.00 Petrolatum (pioner 5464) 2S.OO propellant (1681) RESULTS Control: 100.00 100.00 1OOOO FOAM propellant (1681- 8.00 8.OO propane + butane + isobutane) foam quality G Fluorocarbon Dymel 134 ap 1S.OO Color White RESULTS Odor no odor FOAM shakability Good Collapse time (36 C-sec.) 3OO.G foam quality P P P bubble mean size (Lm) 105.00 Color white white white Bubbles above 500 m (%) O.OO Odor no odor no odor no odor PFF Shakability good good good Collapse time (RT-sec.) <2O <10 <2O viscosity S166.90 PFF centrifugation (1K) separation Viscosity S934.00 1011.78 S934.OO centrifugation (1K) separation stable separation TABLE 21 P = Poor Comparative compositions that do not provide foam of any quality (0647 The EXA-based formulations broke down immedi EXA2 EXA3 EXA2 ately and did not produce good foams. Changing the propel pressurized Pressurized pressurized lent did not help In contrast previous MCH-based formula with with with tions produced good quality foams which had a collapse time Hydrocarbon hydrocarbon fluorocarbon in excess of 4-5 minutes. Caprylic Capric Triglyceride 25.50 24.50 25.50 0648. Additionally, the results with minocycline and light Mineral Oil 8.OO 11.00 8.00 doxycycline provide indications of stable formulations for Cyclomethicone 2O.OO 32.OO 2O.OO topical administration of tetracycline antibiotics that may Beeswax 1...SO 1...SO 1...SO Sorbitan Monooleate (span 4...SO 6.OO 4SO also include stable active ingredients. 80) 0649. Additional minocycline formulations are provided in the following Tables 22 to 25 TABLE 22 Additional formulations of Minocycline HCl foam PMCHOO1 PMCHOO2 PMCHOO3 PMCHOO4 PMCHOOS PPG-15 Stearyl ether S.OO SO.OO 84.32 Octyldodecanol 12.00 12.00 12.00 40.OO Light Mineral Oil 67.32 22.32 72.32 44.32 Glycerol Monostearate 6.OO 6.OO 6.OO 6.OO 6.OO Stearyl alcohol 6.OO 6.OO 6.OO 6.OO 6.OO Myristyl alcohol 2.50 2.50 2.50 2.50 2.50 Minocycline HCI 1.18 1.18 1.18 1.18

Total 1OOOO 1OOOO 100.00 1OOOO Propellant (1681) 12.00 12.00 12.00 12.00 Results

Viscosity 7934.31 121894 14412.92 10925.67 2783.41 Quality G G FG G FG to G Color slight slight slight slight slight yellow yellow yellow yellow yellow Odor no odor v.fodor v.fodor no odor no odor Shakability 2 2 2 2 2 collapse time 3OOG >3OOFG NR 18OFG Density O.127 O.138 NR O.100 bubble size (Lm) 96 88 40S 100.00 186.OO bubble size (above 500 m) O O 26.9 3.30 G = Good; FG= Fairly Good US 2010/031 0476 A1 Dec. 9, 2010 53

Comments: Comments: 0650 The influence of PPG-15 Stearyl ether concentra 0655 The same conclusion as was previously made tions foam quality was tested in formulations PMCH-001 to regarding PPG-15 stearyl ether could be applied regarding the PMCH-003. The study revealed that at concentration of influence of octyldodecanol concentration on MCH foam around 80% w/w foam quality failed down from good to quality namely: high concentration of octyldodecanol fairly good. reduces foam quality. Addition of oleyl alcohol in Substantial 0651) Formulation showed good foam quality without amounts reduced the foam quality. PPG-15 stearyl ether and minimal concentration of octyl TABLE 24 dodecanol (see examples PMCH 004 and 005). 0652 This result means that we can produce high quality Additional formulations of Minocycline HCl foam (Continued foam without PPG-15 Stearyl ether. PMCHO12 PMCHO13 PMCHO14 PMCHO15 Manufacturing Procedure for PMCH001 to PMCH 018 for PPG-15 Stearyl 1S.OO 1S.OO mulations ether Octyldodecanol 12.00 12.00 12.00 12.00 0653 Heat all ingredients to 70° C. to complete dissolu Oleyl alcohol 67.32 22.32 tion. Cyclomethicone S.OO SO.OO 3.00 3.00 Jojoba oil 54.32 0654 Cool to 25°C. Add Minocycline by continuous stir Peppermint oil 54.32 ring.

TABLE 23

Additional formulations of Minocycline HCl foam (Continued)

PMCHOO6 PMCHOO7 PMCHOO8 PMCHOO9 PMCHO10 PMCHO11

PPG-15 Stearyl 12.00 12.00 ether Octyldodecanol S.OO SO.OO 84.32 12.00 12.00 Oleyl alcohol S.OO SO.OO 84.32 Light Mineral Oil 67.32 22.32 67.32 22.32 Glycerol 6.OO 6.OO 6.OO 6.OO 6.OO 6.OO Monostearate Stearyl alcohol 6.OO 6.OO Myristyl alcohol 2.50 2.50 Minocycline HCl 1.18

Total 1OOOO 1OOOO Propellant 12.00 12.00 (1681) Results

Viscosity 433S.O7 S102.91 SS82.81 S422.84 1985.57 668.86 Quality G G F G FG Color slight slight slight slight slight slight yellow yellow yellow yellow yellow yellow Odor no odor no odor no odor no odor no odor no odor Shakability 2 2 2 2 2 collapse time >3OOG 3OOFG NR >30OFG NR NR Density 0.137 O.151 NR O.103 NR NR bubble size (Lm) 18O.OO 18S.OO NR 142 212 NR bubble size O.OO 3.60 O 7.1 (above 500 m)

G = Good; FG= Fairly Good; F = Fair; P = Poor US 2010/031 0476 A1 Dec. 9, 2010 54

TABLE 24-continued TABLE 25 Additional formulations of Minocycline HCl foam (Continued Additional formulations of Minocycline HCl foam PMCHO12 PMCHO13 PMCHO14 PMCHO15 PMCHO17- PMCHO17 PMCHO17 PMCHO17 Placebo (1% API) (5% API) (10% API) Glycerol 6.OO 6.OO 6.OO 6.OO Monostearate PPG-15 Stearyl 1S.OO 14.82 14.25 13.50 Stearyl alcohol 6.OO 6.OO 6.OO 6.OO ether Myristyl alcohol 2.50 2.50 2.50 2.50 Octyldodecanol 12.00 11.86 1140 10.80 Minocycline HCl 1.18 1.18 1.18 1.18 Cyclomethicone 3.00 2.96 2.85 2.70 Light Mineral Oil 55.50 54.85 52.72 49.95 Total 1OOOO 100.00 100.00 1OOOO Glycerol 6.OO 5.93 5.70 S.40 Propellant 12.00 12.00 12.00 12.00 Monostearate (1681) Stearyl alcohol 6.OO 5.93 5.70 S.40 Results Myristyl alcohol 2.50 2.47 2.38 2.25 Minocycline HCl 1.18 S.OO 10.00 Viscosity 139.97 5454.84 8O3O.23 221.9S Quality F FG G P Total 1OOOO 100.00 100.00 100.00 Color slight slight slight slight Propellant 12.00 12.00 12.00 12.00 yellow yellow yellow yellow (1681) Odor no odor no odor no odor mental Results Shakability 2 2 2 2 collapse time NR NR Viscosity 7630.37 2543.45 7918.31 27O3.42 Density NR NR NR NR Quality G G G G bubble size (Lm) 148 NR 55 Color white slight yellow yellow bubble size 3.8 O yellow (above 500 m) Odor no odor no odor no odor no odor Shakability 2 2 2 2 G = Good; collapse time 190.F 24OF 3OOFG >3OOFG FG= Fairly Good; Density 0.077 O. 117 O. 120 O.143 F = Fair; P = Poor G = Good; FG= Fairly Good; Comments: F = Fair; P = Poor 0656 High concentrations of cyclomethicone destroyed the foam. Comments: 0657 Addition of therapeutic oils like jojoba oil revealed good foam quality. Addition of peppermint oil totally 0658 Impact of various concentrations of Minocycline destroyed the foam (see formulations PMCH014 and 015) HCl on foam quality was tested in formulations PMCH-016 (1% API); (5% API), (10% API). Addition of higher concen tration of Minocycline HCl to placebo formulation did not TABLE 24A improve the foam quality. Additional formulations of Minocycline HCl foam 0659 Formulations PMCH 017 (1% API), (5% API), (10% API) revealed good foam quality as well as placebo PMCHO16- PMCHO16- PMCHO16 PMCHO16 PMCHO17. Placebo (1% API) (5% API) (10% API) 0660 All the formulations herein, which were found to be PPG-15 Stearyl 1S.OO 1S.OO 14.25 13.50 useful carriers for doxycycline or minocycline can be usefully ether Octyldodecanol 12.00 12.00 11.41 10.80 used as carriers for other active agents. In some embodiments Oleyl alcohol 55.50 54.30 52.73 49.95 the active agents may be sensitive and in other embodiments Cyclomethicone 3.00 3.00 2.85 2.70 they may be non sensitive. In certain embodiments they are Glycerol 6.OO 6.OO 5.70 S.40 insoluble and in certain other embodiments they are soluble. Monostearate Stearyl alcohol 6.OO 6.OO 5.70 S.40 By way of a non limiting Example both the minocycline Myristyl alcohol 2.50 2.50 2.38 2.25 formulation MCH-072 and the parallel doxycycline formu Minocycline HCl 1.18 S.OO 1O.OO lation DOX-033, which were found to be compatible with all of Minocycline HCL (MCH), Doxycycline Hyclate or Doxy Total 1OOOO 100.00 100.00 100.00 Propellant (1681) 12.00 12.00 12.00 12.00 cycline Monohydrate (DOX) have also been shown above to Results be a useful carrier with clindamycin phosphate, pimicroli mus, and diclofenac potassium, Calcipotriol, Vitamin A Viscosity 48.99 127.97 6670.58 424.91 acetate, Betamethasone 17-Valerate, CiclopiroXolamine, Quality FG P FG FG Color white slight yellow yellow yellow Benzoyl Peroxide and Coal Tar Extract (ethanol). It follows Odor no odor v.fodor v.fodor v.fodor that other similar formulations based on an oil/silicone/sur Shakability 2 2 2 2 factant composition will also provide excellent carriers for collapse time NR NR NR NR these and other active agents. Density NR NR NR NR

G = Good; Example 5 FG= Fairly Good; Hydration Studies F = Fair; P = Poor 0661 The hydration effect of Placebo PMCH017 formu lation was tested on healthy volunteers by corneometer. The US 2010/0310476 A1 Dec. 9, 2010 55 market anti acne product PanOxyl and moisturizer Cetaphil 0677. It is appreciated that certain features, which are, for cream were tested for comparision. The Placebo formulation clarity, described in the context of separate embodiments, without any active hydration agent was found to improve may also be provided in combination in a single embodiment. hydration of the skin by about 5% and did not cause a skin Conversely, various features, which are, for brevity, described drying effect observed with the PanOxyl cream. in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Although the General Study Design present disclosure has been described in conjunction with 0662 Healthy subjects received one treatment of each of specific embodiments thereof, it is evident that many alterna the study medications and reference products (as applicable) tives, modifications and variations will be apparent to those and were followed up to determine the levels of skin hydra skilled in the art. tion using the Corneometer RCM825 instrument. (Courage+ 1. A topical tetracycline antibiotic composition comprising Khazaka, Germany). a foamable pharmaceutical composition and a propellant, the foamable pharmaceutical composition comprising: Study Flow Chart a) about 0.1% to about 10% by weight of a tetracycline 0663 antibiotic; b) about 60% to about 95% by weight of: at least one oily emollient; at least one oil, wherein the oil is a liquid hydrocarbon Study Activity Baseline 1 hour 3 hours 6 hours based oil; or Application of the test X a combination of at least one oily emollient and at least preparations one oil; Assessment of skin hydration X c) about 0.01% to about 15% by weight of at least one Surfactant, wherein the surface active agent is an ester of Before treatment a C8-C24 saturated hydrocarbon; 0664) Study Procedures d) optionally 0.01% to about 10% by weight of at least one 0665 a. Subjects were presented on the day of the study foam adjuvant, wherein the foam adjuvant is a 14C to one hour ahead of the study initiation. 18C fatty alcohol; and 0666 b. The subjects were accommodated in a calm, wherein each component is tetracycline-compatible; quiet, temperature controlled room (20-24° C.) and wherein the composition is substantially non-aqueous; pleasant surroundings. wherein the tetracycline antibiotic is chemically stable in 0667 c. Subjects were wash their forearms with water the foamable pharmaceutical composition when stored (no soap) and were dry the forearms with dry paper for 72 hours at about at least 25°C. after mixing with the towel. pharmaceutical composition; and 0668 d. Application sites were marked according to wherein the weight ratio of the foamable pharmaceutical one of the following options: composition to the propellant is about 100:5 to about 0669 i. Four squares, 4 cmx4 cm (16 cm2) were 100:35. drawn symmetrically on the forearms of each subject 2. The topical tetracycline antibiotic composition of claim (2 areas on each forearms). Areas were numbered 1, wherein the oily emollient is selected from the group con from 1 to 4. One for each study formulation and one sisting of PPG-15 stearyl ether, octyldodecanol, diisopropyl for the no-treatment (control). adipate, isostearic acid, and cetearyl octanoate. 0670. The formulations were named with letters from B to 3. The topical tetracycline antibiotic composition of claim D (PMCH017P-080113, Cetaphil, PanOxyl) and A (for con 1, wherein the oil is selected from the group consisting of trol). plant-based oil, mineral oil, triglyceride, essential oil, and 0671 e. Each study formulation, as well as control animal-based oil. products and "no-treatment were randomly assigned to 4. The topical tetracycline antibiotic composition of claim the treatment sites according to a randomization list, 3, wherein the oil is selected from the group consisting of provided by the study statistician. light mineral oil, MCT oil, hydrogenated castor oil.jojoba oil, 0672 f. The treatments on each square were blind for and peppermint oil. the study operator. 5. The topical tetracycline antibiotic composition of claim 0673 g. An amount between 40 mg (2.5 mg/cm2) of 1, wherein the surfactant is a stearic acid derived ester; or each of the study formulation, were applied evenly on wherein the surfactant is monoglycerides or diglyceride, the treatment sites according to a randomization list wherein the side chain of the monoglycerides or diglyc 0674 h. Skin hydration level were assessed at baseline erides is a C8-C24 saturated hydrocarbon; or (at least 15 minutes after each subject washed their fore wherein the surfactant is selected from the group consist arms), using the Corneometer(R) CM 825, and then 1 ing of glycerol monostearate, sorbitan monostearate. hour, 3 hours and 6 hours after the application. Three PEG 40 stearate, and PEG 100 stearate. repeated measurements were recorded at each time 6-7. (canceled) point. Results are shown in FIG. 1. 8. The topical tetracycline antibiotic composition of claim 0675 PanOxyl List contains: 5% Benzoyl Peroxide in ofw 1, wherein the foam adjuvant selected from the group con emulsion. sisting of oleyl alcohol, Stearyl alcohol, myristyl alcohol and 0676 Cetaphil contains: water, cetyl alcohol, propylene cocoglycerides. glycol, sodium lauryl sulfate, Stearyl alcohol, methylparaben, 9. The topical tetracycline antibiotic composition of claim propylparaben, butylparaben. 1, wherein the tetracycline antibiotic is selected from the US 2010/031 0476 A1 Dec. 9, 2010 56 group consisting of aminocycline, a doxycycline, minocy c) about 0.01% to about 15% by weight of at least one cline hydrochloride, doxycycline hyclate, and doxycycline Surfactant selected from the group consisting of Glyc monohydrate. erol monostearate, Sorbitan monostearate, hydroge 10. The topical tetracycline antibiotic composition of claim nated castor oil, and PEG 100 Stearate; 1, further comprising at least one of ethanol, aluminum starch d) optionally about 0% to about 10% by weight of at least octenyl Succinate, titanium dioxide, coconut alcohol, and one foam adjuvant selected from the group consisting of hexylene glycol. steryl alcohol, oleyl alcohol, isostearic acid and myry 11. The topical tetracycline antibiotic composition of claim styl alcohol: 1, wherein chemical stability is determined by observing a or B): color change in the foamable pharmaceutical composition; or a) about 0.1% to about 10% by weight of doxycycline wherein chemical stability is determined by measuring at monohydrate; least about 90% by mass of the tetracycline antibiotic at 72 b) about 60% to about 95% by weight of: hours compared to time 0. at least one emollient selected from the group consisting 12. (canceled) of cetearyl octanoate, PPG-15 stearyl ether, propy 13. A topical tetracycline antibiotic composition compris lene glycol, octyldodecanol, diisopropyl adipate, and ing a foamable pharmaceutical composition and a propellant, isostearic acid; the foamable pharmaceutical composition comprising: at least one oil selected from the group consisting of light a) about 0.1% to about 10% by weight of minocycline mineral oil, MCT oil, and hydrogenated castor oil; hydrochloride: or a combination of at least one emollient and at least one b) about 60% to about 95% by weight of: oil; at least one emollient selected from the group consisting c) about 0.01% to about 15% by weight of at least one of PPG-15 stearyl ether, octyldodecanol, diisopropyl Surfactant selected from the group consisting of Glyc adipate, and Cetearyl Octanoate; erol monostearate, Sorbitan monostearate, and PEG at least one oil selected from the group consisting of 100 Stearate; Light mineral oil, MCT oil, Hydrogenated Castor Oil, d) about 1% to about 10% by weight of at least one foam jojoba oil, and peppermint oil; or adjuvant selected from the group consisting of oleyl a combination of at least one emollient and at least one alcohol, Stearyl alcohol, myristyl alcohol and Stearic oil; acid; c) about 0.01% to about 15% by weight of at least one wherein each compound is doxycycline-compatible; Surfactant selected from the group consisting of Glyc wherein the composition is substantially non-aqueous; erol monostearate, Sorbitan monostearate, PEG 40 wherein the doxycycline hyclate or the doxycycline mono Stearate, and PEG 100 Stearate; hydrate is chemically stable in the foamable pharmaceu d) optionally about 0% to about 10% by weight of at least tical composition when stored for 72 hours at about at one foam adjuvant selected from the group consisting of least 25°C. after mixing with the foamable pharmaceu Oleyl alcohol, Stearyl alcohol, Myristyl alcohol and tical composition; and Cocoglycerides; and wherein the weight ratio of the foamable pharmaceutical wherein each component is minocycline-compatible; composition to the propellant is about 100:5 to about wherein the composition is substantially non-aqueous; 100:35. wherein the minocycline hydrochloride is chemically 19-24. (canceled) stable in the foamable pharmaceutical composition 25. The topical tetracycline antibiotic composition of claim when stored for 72 hours at about at least 25° C. after 1, further comprising at about 0.1% to about 5% of a silicone mixing with the carrier or with the agent; and oil. wherein the weight ratio of the foamable pharmaceutical 26. The topical tetracycline antibiotic composition of claim composition to the propellant is about 100:5 to about 25, wherein the silicone oil is cyclomethicone. 100:35. 27. The topical tetracycline antibiotic composition of claim 14-16. (canceled) 1, further comprising at least one tetracycline-compatible 17. The topical tetracycline antibiotic composition of claim additional active agent. 13, wherein chemical stability is determined by measuring 28. A method of treating a bacterial infection, the method less than about 1% by mass of a 4-epiminocylcine at 72 hours comprising topically administering the topical tetracycline compared to time 0. antibiotic composition of claim 1 to a subject in need of 18. A topical tetracycline antibiotic composition compris treatment, wherein the topical antibiotic composition is ing a foamable pharmaceutical composition and a propellant, administered to one or more of skin, face, a mucosal mem the foamable pharmaceutical composition comprising either brane, a body cavity, the nose, the mouth, the eye, the ear A): canal, the respiratory system, the vagina, and the rectum. a) about 0.1% to about 10% by weight of doxycycline 29-30. (canceled) hyclate; 31. A method of treating and preventing post-Surgical b) about 60% to about 95% by weight of: adhesions, the method comprising topically administering at least one emollient selected from the group consisting the topical tetracycline antibiotic composition of claim 1 to a of PPG-15 stearyl ether, diisopropyl adipate, and Cet Surgical site of a Subject. earyl Octanoate; 32-43. (canceled) at least one oil selected from the group consisting of 44. The topical tetracycline antibiotic composition of claim mineral oil and MCT oil; or 1, wherein the tetracycline antibiotic is chemically stable in a combination of at least one emollient and at least one the foamable pharmaceutical composition when Stored for oil; about 3 weeks. US 2010/031 0476 A1 Dec. 9, 2010 57

45. A method of treating a bacterial infection, the method 47. A method of treating and preventing post-Surgical comprising topically administering the topical tetracycline adhesions, the method comprising topically administering antibiotic composition of claim 13 to a subject in need of the topical tetracycline antibiotic composition of claim 13 to treatment, wherein the topical antibiotic composition is a Surgical site of a Subject. administered to skin, a mucosal membrane, or a body cavity. 48. A method of treating and preventing post-Surgical 46. A method of treating a bacterial infection, the method adhesions, the method comprising topically administering comprising topically administering the topical tetracycline the topical tetracycline antibiotic composition of claim 18 to antibiotic composition of claim 18 to a subject in need of a Surgical site of a Subject. treatment, wherein the topical antibiotic composition is administered to skin, a mucosal membrane, or a body cavity. c c c c c