PROPELLANT-FREE TOPICAL SPRAY COMPOSITION OF HALOBETASOL
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.
I3ac.knround of the Invention
I 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 largeskin area and for touchrfiee applications.
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, a buffering agent, a propellant, and water.
U.S. Publication No. 2008102061 55 discloses a non-alcoholic foaming pharmaceutical
I emulsion composition comprising a steroid, an unctuous emollient, and at least one liquefied or
compressed gas propellant.
U.S. 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,
Tmo- -&_ -&-- &.pqI cp&1,.is~pp~~myris@te ad-a- rcwe1lan-t. ,,,,,a,s & r - . - P " L . - - - . - - w ~ - - - .- - .
U.S. Patent 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 ultravateQ and have
been used for the relief of inflammaibry and pruritic manifestations of corticosteroid-responsive
derr~~aluses.
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 propellantfree
topical spray composition of halobetasol comprising halobetasol, an emollient, and a nonaqueous
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 Descri~tiono f 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 nonaqueous
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
- - - - -- 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-f?ee 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
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I
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% wlw to about 0.5% wlw of the total
composition.
The term "emollient", as used herein, refers to a substance that helps to retain the skin'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 fiom 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.,
CrodamolTM G TCC-LQ, ~iglyol@c,a ptexm, LabrafacTML ipophile 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, jojbba oil, and castor oil; cyclomethicone; hydrogenated lanolin; waxes;
lecithin; and mixtures thereof. Preferably, the emollient of the present invention is selected fiom
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 *lo% 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 LLpermeatione nhancer" 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
forrnamide; 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.,p olyethylene glycol 400); ~ranscutol@e;s sential 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 poro'sity 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 &om 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
asse111b1~T. he 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
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.
Ingredients
Halobetasol propionate
Ethyl alcohol
Propylene glycol
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.
Quantity (Oh wlw)
0.05
49.00
50.95 .
Example 2
Procedure:
. ,
1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring.
Ingredients
Halobetasol propionate
Ethyl alcohol
Propylene glycol
Sodium lauryl sulfate
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.
Quantity (% wlw)
0.05
49.00
' 50.85
0.10 .
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 HLIPE or glass container and fitted with a
metered pump assembly.
Example 3
( Ingredients Quantity (% wlw)
I Halobetasol ~ro~ionate I 0.05 I
Ethyl alcohol 49.00
, Polyethylene. glycol 400 . ~ 50.95
Procedure:
I. 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 (% wlw)
Halobetasol propionate 0.05
Ethvl 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 (% wlw)
Halobetasol ~ro~ionate 0.05
Ethyl alcohol 49.00
Caprylic and capric triglycerides 50.00
(CrodamolTMG TCC-LO)
1 Oleic acid 0.95 1
Procedure:
1. Halobctasol propionate was dissolved in a portion of ethyl alcohol while stirring.
2. CrodamolTMG TCC-LQ was added while stirring into the solution of step I .
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
Procedure:
Ingredients
Halobetasol propionate
Ethyl alcohol
Caprylic and capric triglycerides
(CrodamolTMG TCC-LQ) . '
Oleic acid
Sodium lauryl sulfate
1. Halobetasol propionate was dissolved in a portion of ethyl alcohol while stirring.
2. CrodamolTMG TCC-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.
Quantity (% wlw)
0.05
49.00
50.00
0.85
0,lO
6. The solution of step 5 was filled into a HDPE or glass container and fitted with a
metered pump assembly.

WE CLAIM:
1. A propellant-free topical spray composition of halobetasol comprising halobetasol, an
emollient, and a non-aqueous solvent. . .
2. The propellant-fiee topical spray composition of claim 1, wherein the emollient is
selected from the group consisting of polyhydric alcohols, fatty mid triglycerides, fatty
acid esters, fatty acids, oils, cyclomethicone, hydrogenated lanolin, waxes, lecithin, and
mixtures thereof.
3. The propellant-free topical spray composition of clainl 2, whereill lilt: emollient is
selected from the group consisting of polyhydric alcohols, fatty acid triglycerides, and ,
fatty acid esters.
4. The propellant-free 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,
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.
The propellant-free topical spray composition of claim 1, wherein the composition
further comprises solubilizers, permeation enhancers, film-formers, plasticizers,
antioxidants, pH-adjusting agents, or mixtures thereof.
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 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
I (c) dispensing the solution of step (b) in a dispensing system. I
8. A propellant-free topical spray composition of halobetasol comprising halobetasol, an
. - emollient, and a non-aqueous solvent for treating a topical skin condition.
- 4 9. The propellant-free 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.