Patent Publication Number: US-2016235766-A1

Title: Propellant-free topical spray composition of halobetasol

Description:
FIELD OF THE INVENTION 
     The present invention relates to propellant-free topical spray compositions of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent; a process for their preparation; and a method of treating topical skin conditions by administering said propellant-free topical spray compositions. 
     BACKGROUND OF THE INVENTION 
     Semisolid dosage forms, such as creams, ointments, lotions, and gels, are widely used for topical application of active ingredients. However, these are often subject to unintended removal or transfer to other skin surfaces after being applied on the skin. In addition, when a semisolid dosage form is applied on skin, it is typically “rubbed in” which may further irritate the intended site of application. These dosage forms may also cause clogging of pores and therefore block delivery of a quantity of the active ingredient to the skin. 
     Transdermal patches have fixed shapes and sizes and work best on skin areas that are relatively flat and that do not flex or stretch. However, these comprise an occlusive backing membrane which often results in local skin irritation. 
     Pharmaceutical sprays exhibit numerous advantages over other known topical delivery systems. These advantages include the ease with which the formulation can be delivered to the areas of the body that are difficult to treat, the possibility of controlling the dose, and the absence of contamination during use. Further, pharmaceutical sprays are more suitable when application is required on a large skin area and for touch-free applications. 
     U.S. Pat. Nos. 6,126,920 and 7,078,058 disclose betamethasone valerate foamable spray compositions comprising a quick-break foaming agent, an aliphatic alcohol, a fatty alcohol, a surface active agent, a buffering agent, a propellant, and water. 
     U.S. Publication No. 2008/0206155 discloses a non-alcoholic foaming pharmaceutical emulsion composition comprising a steroid, an unctuous emollient, and at least one liquefied or compressed gas propellant. 
     U.S. Publication No. 2008/0107758 discloses a topical spray composition comprising a corticosteroid, an alcohol, a propellant, and a blend of three or more botanic seed oils that are prepared by a cold press method. 
     U.S. Pat. No. 6,579,512 discloses a topical spray composition comprising clobetasol, an alcohol, isopropyl myristate, and a propellant. 
     U.S. Pat. No. 5,972,920 discloses a propellant-free topical spray composition comprising clobetasol, an anionic surfactant, undecylenic acid, and a carrier. 
     Halobetasol is a high potency corticosteroid. Topical dosage forms of halobetasol, such as creams and ointments, are commercially available under the trade name Ultravate® and have been used for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. 
     Although cream and ointment dosage forms of halobetasol have been known for decades, there remains an unmet need for an improved topical composition of halobetasol which overcomes the drawbacks of the available cream and ointment dosage forms and results in better patient compliance when compared to available dosage forms. 
     The present invention teaches topical spray compositions of halobetasol which are propellant-free, inexpensive, and provide enhanced patient compliance. 
     SUMMARY OF THE INVENTION 
     The composition of the present invention is a significant advance over conventional halobetasol compositions, as it permits the application of halobetasol without physical contact with the area of application, except by the spray itself. Further, the composition of the present invention is propellant-free, safe, inexpensive, and results in better patient compliance. 
     The present invention relates to a propellant-free, non-occlusive, non-irritant, quick drying topical spray composition of halobetasol. The present invention includes a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent. It also relates to a process for the preparation of said propellant-free topical spray composition. It further relates to a method of treating a topical skin condition by administering said propellant-free topical spray composition. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     A first aspect of the present invention provides a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent. 
     According to one embodiment of this aspect, there is provided a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent, wherein the emollient is selected from the group consisting of polyhydric alcohols, fatty acid triglycerides, and fatty acid esters. 
     According to another embodiment of this aspect, there is provided a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent, wherein the composition is stable. 
     A second aspect of the present invention provides a dispensing system for administering a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent, wherein the dispensing system comprises a container and a pump assembly. 
     A third aspect of the present invention provides a process for the preparation of a propellant-free topical spray composition of halobetasol, wherein the process comprises the steps of:
         (a) dissolving halobetasol in one portion of a non-aqueous solvent;   (b) mixing an emollient and another portion of the non-aqueous solvent into the solution of step (a); and   (c) dispensing the solution of step (b) in a dispensing system.       

     A fourth aspect of the present invention provides a method of treating a topical skin condition by administering a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent. 
     According to one embodiment of this aspect, there is provided a method of treating a topical skin condition by administering a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent, wherein the condition is selected from the group consisting of dermatoses, psoriasis, eczema, rosacea, acne vulgaris, dermatitis, pruritus, seborrhea, skin cancers, inflammation, and combinations thereof. 
     According to another embodiment of this aspect, there is provided a method of treating a topical skin condition by administering a propellant-free topical spray composition of halobetasol comprising halobetasol, an emollient, and a non-aqueous solvent, wherein the method comprises co-administration of additional drug(s) used to treat topical skin conditions. 
     The term “topical”, as used herein, refers to a composition meant for application to the skin, nail, or mucosal tissue. 
     The term “propellant-free”, as used herein, means that the composition is not delivered in admixture with any of the conventionally used aerosol propellants. 
     The term “spray”, as used herein, means to dispense the composition as a mass or jet of droplets from a dispensing system. 
     The term “stable”, as used herein, means chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40° C. and 75% relative humidity or at 25° C. and 60% relative humidity for a period of at least three months to the extent necessary for the sale and use of the composition. 
     The term “halobetasol”, as used herein, includes halobetasol and its salts, polymorphs, hydrates, solvates, prodrugs, chelates, and complexes. The preferred salt of halobetasol is halobetasol propionate. The propellant-free topical spray composition of the present invention comprises halobetasol in an amount of from about 0.01% w/w to about 0.5% w/w of the total composition. 
     The term “emollient”, as used herein, refers to a substance that helps to retain the skin&#39;s moisture and also helps to control the rate of evaporation and the tackiness of the composition. Additionally, emollients provide a softening or soothing effect on the skin surface. Suitable emollients are selected from the group consisting of polyhydric alcohols such as propylene glycol, butylene glycol, polyethylene glycol (e.g., polyethylene glycol 400), glycerol, and sorbitol; fatty acid triglycerides such as a mixture of caprylic and capric triglycerides (e.g., Crodamol™ GTCC-LQ, Captex®, Labrafac™ Lipophile WL), palmitic triglyceride, oleic triglyceride, caprylic triglyceride, capric triglyceride, and linoleic triglyceride; fatty acid esters such as isopropyl myristate, isopropyl palmitate, dibutyl adipate, and dibutyl phthalate; fatty acids such as oleic acid and stearic acid; oils such as mineral oil, lanolin oil, coconut oil, cocoa butter, olive oil, jojoba oil, and castor oil; cyclomethicone; hydrogenated lanolin; waxes; lecithin; and mixtures thereof Preferably, the emollient of the present invention is selected from the group consisting of polyhydric alcohols, fatty acid triglycerides, and fatty acid esters. 
     The term “non-aqueous solvent”, as used herein, refers to the solvent used to dissolve halobetasol. Suitable non-aqueous solvents are selected from the group consisting of ethyl alcohol, isopropyl alcohol, propylene glycol, butanediol, pentanediol, hexanediol, triethylene glycol, tetraethylene glycol, dipropylene glycol, dibutylene glycol, glycerin, dimethyl isosorbide, tetrahydrofurfuryl alcohol polyethylene glycol ether, N-methyl-2-pyrrolidone, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide, dimethyl acetamide, lactic acid, glycolic acid, methylene chloride, methyl-ethyl-ketone, ethyl acetate, methylene dimethyl ether, and mixtures thereof Preferably, the non-aqueous solvent of the present invention is ethyl alcohol, isopropyl alcohol, or mixtures thereof. In particular, ethyl alcohol is dehydrated ethyl alcohol. 
     The term “about”, as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value. 
     The propellant-free topical spray composition of the present invention further comprises solubilizers, permeation enhancers, film-formers, plasticizers, antioxidants, pH-adjusting agents, or mixtures thereof. 
     The term “solubilizer” as used herein is a substance that aids in the dissolution or dispersion of halobetasol in the composition. Suitable solubilizers are selected from the group consisting of polyhydric alcohols such as propylene glycol and polyethylene glycol, e.g., polyethylene glycol 400; fatty acids such as oleic acid and stearic acid; non-ionic and ionic surfactants such as polyoxyethyl-sorbitan-fatty acid esters such as polysorbates, ethers of sugars, ethoxylated fatty alcohols, sodium lauryl sulfate, taurocholic acid, lecithin, and Labrasol®; vitamin E; vitamin E TPGS (tocopheryl polyethylene glycol 1000 succinate); and mixtures thereof 
     The term “permeation enhancer” as used herein is a substance used to enhance the penetration rate of halobetasol through the skin. Suitable permeation enhancers are selected from the group consisting of lipophilic solvents such as dimethyl sulfoxide and dimethyl formamide; non-ionic and ionic surfactants such as polyoxyethyl-sorbitan-fatty acid esters such as polysorbates, ethers of sugars, ethoxylated fatty alcohols, sodium lauryl sulfate, taurocholic acid, lecithin, and Labrasol®; fatty acid esters such as isopropyl myristate and isopropyl palmitate; fatty acids such as oleic acid and stearic acid; polyhydric alcohols such as propylene glycol and polyethylene glycol (e.g., polyethylene glycol 400); Transcutol®; essential oils such as menthol; and mixtures thereof. 
     The term “film-former” as used herein is a substance that forms a stable film on a topical surface when applied. Suitable film-formers are selected from the group consisting of acrylic polymers or copolymers such as methacrylic acid copolymers; cellulose derivatives such as cellulose acetate, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, methyl cellulose, and ethyl cellulose; polyvinyl acetate; polyvinyl alcohol; povidone; povidone vinyl acetate; and mixtures thereof. These film-formers can partially dissolve on exposure to moisture from the skin or air, the dissolution resulting in the formation of a porous film. This porosity can be enhanced by including additional water-soluble additives. The water-soluble additive is preferably propylene glycol, sodium lauryl sulphate, poloxamers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, cetomacrogol, polyethylene glycol, transcutol, or mixtures thereof. 
     The term “plasticizer” as used herein is a substance that aids the composition in forming a flexible, adherent film on the skin. Suitable plasticizers are selected from the group consisting of citric acid esters, dimethyl isosorbide, castor oil, propylene glycol, polyethylene glycol, glycerol, oleic acid, citric acid, adipic acid, phosphate esters, fatty acid esters, glycol derivatives, hydrocarbons and their derivatives, butanediol polyesters, diethyl phthalate, dibutyl phthalate, chlorinated paraffins, and mixtures thereof 
     Suitable antioxidants are selected from the group consisting of butylated hydroxyl anisole, butylated hydroxy toluene, sodium metabisulfite, ascorbic acid, ascorbyl palmitate, thiourea, acetylcysteine, dithiothreitol, cysteine hydrochloride, propyl gallate, tocopherol, and mixtures thereof. 
     Suitable pH-adjusting agents are selected from the group consisting of pharmaceutically acceptable organic or inorganic acids or bases such as sodium hydroxide, tromethamine, hydrochloric acid, inorganic oxides, inorganic salts of weak acids, and mixtures thereof. 
     In the present invention, the dispensing system comprises a container and a pump assembly. 
     Containers can be made from materials selected from the group consisting of stainless steel, aluminum, plastic, and glass. The plastic container can be made up of high density polyethylene (HDPE). The containers can be coated with inert inner linings of epoxy-phenolic resins, epoxy-urea-formaldehyde resins, polytetrafluoroethylene (PTFE), perfluoroethylene propylene (FEP), perfluoroalkoxy alkane (PFA), ethylene tetrafluoroethylene (ETFE), polyvinylidene fluoride (PVDF), chlorinated ethylene tetrafluoroethylene, or another coating treatment that creates a barrier to chemical interaction between the composition and the container. 
     The pump assembly comprises a spring, a dip tube, a pump dispenser, a chamber, a dust cap, and an actuator. The pump dispenser dispenses the composition through a dip tube into a chamber. The composition is then dispensed through the actuator fitted with an orifice in the form of a substantially uniform spray. In particular, the pump assembly is a metered pump assembly. The metered pump assembly dispenses a metered quantity with each actuation of the actuator. The metered quantity will avoid under-dosing or overdosing that may lead to undesirable side effects. A dust cap is fitted onto the container to shield the contents of the container from the outside environment. 
     The amount of halobetasol may depend upon the purpose for which the composition is to be applied. For example, the dosage and frequency of application can vary depending upon the type and severity of the topical condition. 
     The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention. 
     EXAMPLES 
     Example 1 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Quantity (% w/w) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Halobetasol propionate 
                 0.05 
               
               
                   
                 Ethyl alcohol 
                 49.00 
               
               
                   
                 Propylene glycol 
                 50.95 
               
               
                   
                   
               
            
           
         
       
     
     Procedure: 
     
         
         1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring. 
         2. Propylene glycol was added while stirring into the solution of step 1. 
         3. The remaining quantity of ethyl alcohol was added into the solution of step 2 and mixed. 
         4. The solution of step 3 was filled into a HDPE or glass container and fitted with a metered pump assembly. 
       
    
     Example 2 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Quantity (% w/w) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Halobetasol propionate 
                 0.05 
               
               
                   
                 Ethyl alcohol 
                 49.00 
               
               
                   
                 Propylene glycol 
                 50.85 
               
               
                   
                 Sodium lauryl sulfate 
                 0.10 
               
               
                   
                   
               
            
           
         
       
     
     Procedure: 
     
         
         1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring. 
         2. Propylene glycol was added while stirring into the solution of step 1. 
         3. Sodium lauryl sulfate was added while stirring into the solution of step 2. 
         4. The remaining quantity of ethyl alcohol was added into the solution of step 3 and mixed. 
         5. The solution of step 4 was filled into a HDPE or glass container and fitted with a metered pump assembly. 
       
    
     Example 3 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Quantity (% w/w) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Halobetasol propionate 
                 0.05 
               
               
                   
                 Ethyl alcohol 
                 49.00 
               
               
                   
                 Polyethylene glycol 400 
                 50.95 
               
               
                   
                   
               
            
           
         
       
     
     Procedure: 
     
         
         1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring. 
         2. Polyethylene glycol 400 was added while stirring into the solution of step 1. 
         3. The remaining quantity of ethyl alcohol was added into the solution of step 2 and mixed. 
         4. The solution of step 3 was filled into a HDPE or glass container and fitted with a metered pump assembly. 
       
    
     Example 4 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Quantity (% w/w) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Halobetasol propionate 
                 0.05 
               
               
                   
                 Ethyl alcohol 
                 49.00 
               
               
                   
                 Polyethylene glycol 400 
                 50.85 
               
               
                   
                 Sodium lauryl sulfate 
                 0.10 
               
               
                   
                   
               
            
           
         
       
     
     Procedure: 
     
         
         1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring. 
         2. Polyethylene glycol 400 was added while stirring into the solution of step 1. 
         3. Sodium lauryl sulfate was added while stirring into the solution of step 2. 
         4. The remaining quantity of ethyl alcohol was added into the solution of step 3 and mixed. 
       
    
     5. The solution of step 4 was filled into a HDPE or glass container and fitted with a metered pump assembly. 
     Example 5 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Quantity (% w/w) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Halobetasol propionate 
                 0.05 
               
               
                   
                 Ethyl alcohol 
                 49.00 
               
               
                   
                 Caprylic and capric triglycerides 
                 50.00 
               
               
                   
                 (Crodamol ™ GTCC-LQ) 
               
               
                   
                 Oleic acid 
                 0.95 
               
               
                   
                   
               
            
           
         
       
     
     Procedure: 
     
         
         1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring. 
         2. Crodamol™ GTCC-LQ was added while stirring into the solution of step 1. 
         3. Oleic acid was added while stirring into the solution of step 2. 
         4. The remaining quantity of ethyl alcohol was added into the solution of step 3 and mixed. 
         5. The solution of step 4 was filled into a HDPE or glass container and fitted with a metered pump assembly. 
       
    
     Example 6 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Quantity (% w/w) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Halobetasol propionate 
                 0.05 
               
               
                   
                 Ethyl alcohol 
                 49.00 
               
               
                   
                 Caprylic and capric triglycerides 
                 50.00 
               
               
                   
                 (Crodamol ™ GTCC-LQ) 
               
               
                   
                 Oleic acid 
                 0.85 
               
               
                   
                 Sodium lauryl sulfate 
                 0.10 
               
               
                   
                   
               
            
           
         
       
     
     Procedure: 
     
         
         1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring. 
         2. Crodamol™ GTCC-LQ was added while stirring into the solution of step 1. 
         3. Oleic acid was added while stirring into the solution of step 2. 
         4. Sodium lauryl sulfate was added while stirring into the solution of step 3. 
         5. The remaining quantity of ethyl alcohol was added into the solution of step 4 and mixed. 
         6. The solution of step 5 was filled into a HDPE or glass container and fitted with a metered pump assembly.