The present invention relates to topical spray compositions comprising halobetasol, an
emollient, a non-aqueous solvent, and a propellant; a process for their preparation; and a method
. of treating a topical skin condition by administering said topical spray compositions.
Background of thc Invcntion
!
! Many delivery systems, including creams, ointments, lotions, gels, transdermal patches,
I
I and sprays, are currently available for the topical application of active ingredients.
Amongst these, semisolid dosage forms such as creams, ointments, lotions, and gels are
widely used. 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 suitable
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. ow ever, 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, sprays are more suitable when application is
required for a large area of skin and therefore result in enhanced patient compliance.
U.S. 'Patent 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, buffering agent, water, and a propellant.
U.S. Patent No. 7,645,803 discloses a foamable spray composition comprising a
saccharide, a surface active agent, a polymeric agent, a gelling agent, a .film-forming agent,
water, and a propellant. .
U.S. Publication No. 2008102061'55 discloses a non-alcoholic foaming pharmaceutical
emulsion composition comprising a steroid, an unctuous emollient, and at least one liquefied or
compressed gas propellant.
US. Publication No. 200810107758 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. Patent No. 6,579,5 12 discloses a topical spray composition comprising clobetasol,
an alcohol, isopropyl myristate, and a propellant.
Halobetasol is a high potency corticosteroid. Topical dosage forms of halobetasol, such
as creams and ointments, are commercially available under the trade name ultravateB 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 ointhent dosage forms and results in better
patient compliance.
The present invention teaches topical spray compositions of halobetasol which are nonocclusive,
non-irritant, and provide enhanced patient compliance.
Summary of the invention
The compositions of the present invention are a significant advance over conventional
halobetasol compositions, since they allow for the application of halobetasol with no physical
contact to the area of application, except by the spray itself.
The present invention relates to non-occlusive, non-irritant, quick drying topical spray
compositions of halobetasol. The present invention includes a topical spray composition of
halobetasol comprising halobetasol, an emollient, a non-aqueous solvent, and a propellant. It
also relates to a process for the preparation of said topical spray composition. It further relates
to a method of treating topical skin conditions by administering said topical spray composition.
Detailed Description of the Invention
A first aspect of the present invention provides a topical spray composition of
halobetasol comprising halobetasol, an emollient, a non-aqueous solvent, and a propellant.
i According to one embodiment of this aspect, there is provided a topical spray
composition of halobetasol comprising halobetasol, an emollient, a non-aqueous solvent, and a
propellant, wherein the emollient is selected from the group consisting of fatty acid triglycerides,
fatty acid esters, and polyhydric alcohols.
According to another embodiment of this aspect, there is provided a topical spray
composition of halobetasol comprising halobetasol, an emollient, a non-aqueous solvent, and a
prope1lant;wherein the composition is stable.
A second aspect of the present invention provides a dispensing system for administering
a topical spray composition of halobetasol comprising halobetasol, an emollient, a non-aqueous
solvent, and a propellant, wherein the dispensing system comprises a container and a valve
assembly.
A third aspect of the present invention provides a process for the preparation of a topical
spray composition of halobetasol comprising:
(a) dissolving halobetasol in one portion of a non-aqueous solvent to form a solution;
(b) mixing an emollient and another portion of the non-aqueous solvent into the
solution of step (a); - -
(c) dispensing the solution of step (b) in a dispensing system; and
(d) charging a propellant in the dispensing system of step (c).
A fourth aspect of the present invention provides a method of treating a topical skin
condition by adininistering a topical spray composition of halobetasol comprising halobetasol,
an emollient, a non-aqueous solvent, and a propellant;
According to one embodiment of this aspect, there is provided a method of treating a
topical skin condition by administering a topical spray composition of halobetasol comprising
halobetasol, an emollient, a non-aqueous solvent, and a propellant, 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 topical spray composition of halobetasol comprising
halobetasol, an emollient, a non-aqueous solvent, and a propellant, wherein the method
comprises co-administration of at least one additional drug 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 "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
sale and use of 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 topical spray composition of the present invention comprises
halobetasol in an amount 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 retain skin moisture
and also helps control the rate of evaporation and the tackiness of the composition.
Additionally, emollients provide a softening or soothing effect on the skin surface. Suitable
examples of emollients are selected from the group consisting of fatty acid triglycerides such as
mixtures of caprylic and capric triglycerides (e.g., CrodamolTM G TCC-LQ, ~ i ~ l ~ o cla'p,t exB,
LabrafacTM 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; polyhydric alcohols such as propylene glycol,
butylene glycol, polyethylene glycol, glycerol, and sorbitol; fatty acids such as oleic acid and
stearie acid; oils such as mineral oil, lanolin oil, coconut oil, cocoa butter, olive oil, jojoba oil,
and castor oil; cyclomethicone; hydrogenated lanolin; waxes; lecithin; or mixtures thereof.
Preferably, the emollient is selected from the group consisting of fatty acid triglycerides, fatty
acid esters, and polyhydric alcohols.
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, dipro ylene gycol, dibutylene ycol, glycerin, dimethyl
--- -q2pz=6r;:FB=+b -- =a=- 2-rix q=a=Lr+T+. -
5
isosorbide, tetrahydro hrfuryl 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 dimeth.yl ether, and mixtures
thereof. In particular, ethyl alcohol is dehydrated ethyl alcohol.
The term "propellant", as used herein, refers to the substance that helps in propelling the
composition out of the container. Suitable examples of propellants are selected from the group
consisting of conventional, non-ozone depleting hydrocarbon propellants, including propane,
butane, isobutane, . cyclopropane, 1,1,1,2- tetrafluorethane, 1,1,1,2,3,3,3- heptafluoropropane,
1,l- difluoroethane, 1,1,1,3,3,3- hexnfluoropropanc, and mixtures thereof; fluorocarbon gas; and
liquefied petroleum gas.
The term "about", as used herein, refers to any value which lies within the range defined
by a variation of up to *lo% of the value.
The 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; fatty acids
such as oleic acid and stearic acid; non-ionic and ionic surfactants such as polyoxyethylsorbitan-
fatty acid esters such as polysorbates, ethers of sugars, ethoxylated fatty alcohols,
sodium lauryl sulfate, taurocholic' acid, lecithin, and ~abrasol~vi;ta min E; vitamin E TPGS
(tocopheryl polyethylene glycol 1000 succinate); or combinations 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 ~abrasol~fa;t ty 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.,p olyethylene glycol 400); ~ranscutol@e;s sential oils, e.g.,
menthol; and combinations 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 .
combinations thereof. These film-formers can partially dissolve on exposure to moisture from
the skin or air, resulting in the formation of a porous film. The 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 combinations 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, phosphate esters, fatty acid esters, glycol derivatives,
hydrocarbons and their derivatives, adipic acid, butanediol polyesters, diethyl phthalate, dibutyl
phthalate, chlorinated paraffins, and combinations 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
combinations 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 combinations thereof.
In the present invention, the dispensing system comprises a container and a valve
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 an inert inner lining of epoxy-phenolic
resins, epoxy-urea-formaldehyde resins, polytetrafluoroethylene . (PTFE), perfluoroethylenepropylene
(PFEP), 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 valve assembly may comprise a valve, a spring, a dip tube, an actuator, and a dust
cap. Various types of valves such as continuous spray valves and metering valves can be used.
The metered valve dispenses a metered quantity of formulation with each actuation of the
actuator. he metered quantity avoids 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 depends 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
. Procedure: I
Ingredients
Halobetasol propionate
Ethyl alcohol
Isopropyl myristate
Liquefied petroleum gas
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
Quantity (% wlw)
0.05
52.65
7.30
40.00
2. Isopropyl myristate is added while stirring into the solution of step 1.
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and the 1
container is fitted with a valve assembly. I
5. Liquefied petroleum gas is charged into the filled container of step 4.
Procedure:
Example 2
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
Ingredients
Halobetasol propionate
Ethyl alcohol
Isopropyl myristate
Isobutane
2. Isopropyl myristate is added while stirring into the solution of step 1.
Quantity (% wlw)
0.05 -
32.65
7.30
60.00
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed. . .
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Isobutane is charged into the filled container of step 4.
Procedure:
Example 3
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
Ingredients
Halobetasol propionate
Ethyl alcohol
Isopropyl myristate
Butane
2. Isopropyl myristate is added while stirring into the solution of step 1.
Quantity (O/O wlw)
0.05
32.65
7.30
60.00
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Butane is charged into the filled container of step 4.
Example 4
Ingredients Quantity (% w/w)
Halobetasol propionate 0.05
Ethyl alcohol 32.65
Isopropyl myristate 7.30
Propane 60.00
Procedure:
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
2. Isopropyl myristate is added while stirring into the solution of step 1.
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Propane is charged into the filled container of step 4.
Example 5
Ingredients Quantity (% w/w)
Halobetasol propionate 0.05
Ethyl alcohol 52.65
Isopropyl palmitate 7.30
Liquefied petroleum gas 40.00
Procedure:
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol with stirring.
2. Isopropyl palmit&e is added while stirring into the solution of step I.
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Liquefied petroleum gas is charged into the filled container of step 4.
Example 6
Ingredients Quantity (% wlw)
Halobetasol propionate 0.05
Ethyl alcohol 32.65
Isopropyl palmitate 7.30
Isobutane 60.00
Procedure:
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
2. Isopropyl palmitate is added while stirring into the solution of step 1.
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Isobutane is charged into the filled container of step 4.
Example 7
Ingredients Quantity (% w/w)
Halobetasol propionate 0.05
Ethyl alcohol 19.95
Propylene glycol 30.00
Isobutane 50.00
Procedure:
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
2. Propylene glycol is added while stirring into the solution of step 1.
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Isobutane is charged into the filled container of step 4.
Example 8
Ingredients Quantity (% wlw)
Halobetasol pro-pionate 0.05
Ethyl alcohol 19.95
Propylene glycol 30.00
Liquefied petroleum gas 50.00
Procedure:
1. Halobetasol propionate is dissolved into a portion of ethyl alcohol while stirring.
2. Propylene glycol is added while stirring into the solution of step 1.
3. The remaining quantity of ethyl alcohol is added into the solution of step 2 and
mixed.
4. The solution of step 3 is filled into an aluminum container with an inert liner, and
the container is fitted with a valve assembly.
5. Liquefied petroleum gas is charged into the filled container of step 4.
Example 9
Ingredients Quantity (% 'wlw)
Halobetasol propionate 0.05
Ethyl alcohol 42.65
Isopropyl palmitate 7.30
Liquefied petroleum gas 50.00
Procedure:
1. Halobetasol propionate was dissolved into a portion of ethyl alcohol while stirring.
2. Isopropyl palmitate 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 an aluminum container with an inert liner, and
the container was fitted with a valve assembly.
5. Liquefied petroleum gas was charged into the filled container of step 4.
Example 10
Procedure: I
Ingredients
Halobetasol propionate
Ethyl alcohol
Isopropyl palmitate
Isobutane
1. Halobetasol propionate was dissolved into a portion of ethyl alcohol while stirring. 1
Quantity (% wlw)
0.05
42.65
7.30
50.00
2. Isopropyl palmitate was added while stirring into the solution of step 1. I
3. The remaining quantity of ethyl alcohol was added into the solution of step 2 and . I
mixed.
4. The solution of step 3 was filled into an aluminum container .with an inert liner, and
the container was fitted with a valve assembly.
5. Isobutane was charged into the filled .container of step 4.
Example 11
Procedure:
Ingredients
Halobetasol propionate
Ethyl alcohol
Caprylic and capric triglycerides
(CrodamolTM GTCC-LQ)
Isobutane
1. Halobetasol propionate was dissolved into a portion of ethyl alcohol while stirring.
Quantity (% wlw)
0.05
20.00
29.95
50.00
2. CrodamolTMG TCC-LQ 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 an aluminum container with an inert liner, and
the container was fitted with a valve assembly.
5. Isobutane was charged into the filled container of step 4.
Example 12
Procedure:
Ingredients
Halobetasol propionate
~th~i-alcohol
Caprylic and capric triglycerides
(CrodamolTM GTCC-LQ)
Liquefied petroleum gas
1. Halobetasol propionate was di3soIvcd into a portioil of ethyl alcul~ulw ilh stirring.
2. CrodamolTMG TCC-LQ was clddcd whilc stirring into the sululiu~ul f slep 1.
Quantity (% wlw)
0.0.5
20.00
29.95
50.00
3. The remaining quantity of ethyl alcohol was added into the solution of step 2.
4. The Solution of step 3 was filled into an aluminum container with an inert liner, and
the container was fitted with a valve assembly.
5. Liquefied petroleum gas was charged into the filled container of step 4.

WE CLAIM:
1. A topical spray composition of halobetasol comprising halobetasol, an emollient, a nonaqueous
solvent, and a propellant.
2. The topical spray composition of claim 1, wherein the emollient is selected from the
group consisting of fatty acid triglycerides, fatty acid esters, polyhydric alcohols, fatty
acids, oils, cyclomcthiconc, hydrogcnatcd lanolin, waxes, lecithin, or lnixtures tlielqeof.
3. The topical spray composition of claim 2, wherein the emollient is selected from the
group consisting of fatty acid triglycerides, fatty acid esters, and polyhydric alcohols.
4. ' The topical spray composition of claim 1, wherein the non-aqueous solvent is 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, tetrahydro fbrhryl alcohol
polyethylene glycol ether, N-methyl-2-pyrrolidone, 1-methyl-2-pyrrolidinone, dimethyl
sulfoxide, dimethyl acetamide, lactic acid, glycolic acid, methylene chloride, methylethyl-
ketone, ethyl acetate, methylene dimethyl ether, and mixtures thereof.
5. The topical spray composition of claim 1, wherein the propellant is selected from the
group consisting of propane, butane, isobutane, cyclopropane, 1,1,1,2 tetrafluorethane,
1,1,1,2,3,3,3 heptafluoropropane, 1,1, difluoroethane, 1,1,1,3,3,3 hexafluoropropane,
fluorocarbon gases, liquefied petroleum gas, and mixtures thereof.
6. The topical spray composition of claim 1, wherein the composition fbrther comprises
solubilizers, permeation enhancers, film-formers, plasticizers, antioxidants, pH-adjusting
agents, or mixtures thereof.
7. A dispensing system for administering topical spray composition of halobetasol
comprising halobetasol, an emollient, a non-aqueous solvent, and a propellant, wherein j
the dispensing system comprises a container and a valve assembly. I
I
I 8. A process for the preparation of a topical spray composition of halobetasol, wherein the 1
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);
(c) dispensing the solution of step (b) in a dispensing system; and
(d) charging a propellant in the dispensing system of step (c).
i
I .
I 9. A topical spray composition of halobetasol comprising halobetasol, an emollient, a non- I
aqueous solvent, and a propellant for treating a topical skin condition.
1
10. The topical spray composition of claim 9, 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.