COMPOSITION COMPRISING A RETINOID AND BENZOYL PEROXIDE
Field of the Invention
The present invention relates to a stable topical aqueous composition of adapalene in
combination with benzoyl peroxide comprising one or more gelling agent, wherein at least one of
the gelling agent is a carbomer. It also relates to processes for preparing such composition.
Background of the Invention
Acne is a disease of the skin in which the pilosebaceous structures of the skin become
inflamed, leading to the formation of comedones, pustules and nodules. It is generally believed that
acne arises when hyperkeratosis of the pilosebaceous structure wholly or partially blocks the
opening of the structure, resulting in comedones filled with seburn, keratin and Propionibacterium
acnes ("P. acnes"). These lesions are commonly identified as acne. P. acnes naturally occur in
normal skin, but is especially and characteristically present in acne lesions. It is believed that
metabolic by-products and waste from P. acnes within the pilosebaceous structures cause or
contribute to the inflammation of acne lesions.
Conventional acne treatments have been available as oral and topical dosage forms. Oral
drugs include antibiotics like tetracycline, minocycline, doxycycline and erythromycin. Topical
agents for the treatment of acne include retinoids like tretinoin and adapalene; sulfur; resorcinol;
salicylic acid; benzoyl peroxide and antibiotics like erythromycin, clindamycin or tetracycline.
Antimicrobial resistance to topical therapy is becoming an important factor in the treatment
of acne, and clinically an association between the presence of antimicrobial resistant organisms and
therapeutic failure has been observed. The concomitant administration of two or more anti-acne
agents prevent the development of resistant microorganisms and proves to be more effective in the
treatment of acne.
One currently available combination product is ~ ~ i d u oto"p ical gel i alder ma ~abs)w, hich contains
0.1% of adapalene and 2.5% of benzoyl peroxide. Other combination products are Benzarnycin"
topical gel (Dermik Laboratories, Berwyn, Pa.), which contains 3% of erythromycin and 5% of
benzoyl peroxide and Benzaclin" topical gel (Sanofi Aventis), which contains 1 % of clindamycin
phosphate and 5 % of benzoyl peroxide.
It has been noted that the combination of benzoyl peroxide and retinoids shows synergism
in the treatment of acne. Benzoyl peroxide acts by destroying P. acnes, the bacteria that causes the
condition acne. It acts as an antiseptic and as an oxidizing agent, reducing the number of
comedones, or blocked pores. Retinoids allow the keratin plugs of microcomedones to be expelled,
thus fewer lesions are able to rupture and cause papules, pustules and nodules of inflammatory
3
acne. A combination drug of benzoyl peroxide and retinoid should have both comedogenesis and
bacteriostatic effect in acne treatment. Compositions and methods for the treatment of acne
comprising benzoyl peroxide andlor a retinoid have been described in U.S. Patent Nos. 4,350,681;
4,36 1,584; 4,387,107; 4,497,794; 4,67 1,956; 4,960,772; 5,086,075; 5,145,675; 5,466,446;
5,632,996; 5,767,098; 5,851,538; 5,955,109; 5,879,716; 5,955,109; 5,998,392; 6,013,637 and
6,117,843; U.S. Publication Nos. 2003101 70196; 20021064541 and 200510037087.
There have been many difficulties in formulating products containing a combination of
retinoid and benzoyl peroxide. The stability of benzoyl peroxide is greatly influenced by the
chemical composition of the formulation and by storage temperature. Benzoyl peroxide is
extremely reactive and degrades in solution at low temperature on account of the instability of its
peroxide bond. Hence it is difficult to formulate benzoyl peroxide composition in solution form. In
order to limit the problem of rapid instability of benzoyl peroxide in solution, it has been found to
be advantageous to formulate benzoyl peroxide in dispersed form. However, this type of
formulation is not entirely satisfactory since degradation of the benzoyl peroxide in the finished
product is still observed.
A fbrther obstacle in formulating the combination is instability of retinoids in the presence
of benzoyl peroxide. Most of the retinoids are prone to oxidation, and since benzoyl peroxide is a
strong oxidizing agent, the compatibility of these compounds in the same formulation poses
numerous problems in terms of physical and chemical stability.
It is desirable to provide products combining the activity of a retinoid with the activity of
benzoyl peroxide, with few or none of the disadvantages described above. Such compositions
should provide improved compositions which are less irritating, easy to formulate, have smooth
consistency after formulation, are adequately stable, and have a sufficiently long storage life with
or without refrigeration.
A number of documents disclose formulations comprising combination of benzoyl peroxide
and adapalene with particular gelling agents. For example, U.S. Patent Nos. 7,820,186 and
7,964,202; U.S. Publication Nos. 200810176954 and 201110070274 disclose combination
formulations formulated with Simulgel 600 gelling agent. U.S. Publication Nos. 201 110003894 and
201010143285 disclose combinations comprising carrageenan gelling agent and polyurethane
polymer respectively. U.S. Publication No. 201 0/0022642 discloses gelling system comprising two
categories of compounds selected from silicates, cellulose gelling agents and polysaccharide gums.
U.S. Publication Nos. 200910318550 and 201010166852 disclose many gelling agents
including polyacrylamides and polysaccharides and in particular teach away from the use of
carbomer for combination composition of adapalene and benzoyl peroxide. It is being stated that
the use of carbomer in aqueous composition does not give good results in terms of chemical
4
a stability of the benzoyl peroxide or in terms of rheological stability. However, the present inventors
have developed a stable topical composition comprising a combination of retinoid with benzoyl
peroxide and a carbomer gelling agent.
Summary of the Invention
The present invention relates to a stable topical aqueous composition of adapalene in
combination with benzoyl peroxide comprising one or more gelling agent, wherein at least one of
the gelling agent is a carbomer.
In one aspect, the present invention relates to a stable topical aqueous composition having a
pH of about 4 to about 6.5 comprising:
(a) a therapeutically effective amount of retinoid;
(b) a therapeutically effective amount of benzoyl peroxide;
(c) one or more pharmaceutically acceptable excipient(s); and
(d) one or more gelling agent, wherein at least one of the gelling agent is a carbomer.
Embodiments of the composition may include one or more of the following features. For
example, the topical aqueous composition of the present invention is in the form of a gel, solution,
foam, lotion or spray. More particularly the topical aqueous composition of the present invention is
in the form of a gel.
In another embodiment, adapalene is present in a concentration from about 0.001% to about
20% and benzoyl peroxide is present in a concentration from about 0.001% to about 20% by weight
of the composition. More particularly, adapalene is present in a concentration from about 0.01% to
about 10% and benzoyl peroxide is present in a concentration from about 0.01% to about 20% by
weight of the composition.
In an alternate embodiment, the composition comprises a retinoid other than adapalene. The
retinoid is selected from the natural or synthetic retinoid comprising tazarotene, retinoic acid,
tretinoin, isotretinoin, bexarotene, alitretinoin, vitamin A, retinol, retinal, retinyl palmitate, retinyl
acetate, 6-(2-4,4-thiochroman-6-yl)-ethynyl)-3-pyridylmethanol2,- (2-(4,4-dimethyl thiochroman-
6-y1)-ethyny1)-5-pyridinecarboxaldehyde, ethyl 5-(2-(4,4-dimethylthiochroman-6-
y1)ethynyl)thiophene-2-carboxylate, or salts or derivatives thereof.
According to another embodiment, the carbomer gelling agent alone or in combination with
other gelling agent(s) is present in a concentration of about 0.001% to about 30%, particularly in a
concentration of about 0.01% to about lo%, more particularly in a concentration of about 0.1% to
about 5% by weight of the composition.
According to another embodiment, the composition further comprises a film-forming agent.
According to another embodiment, the composition comprises one or more
5
phmaceutically acceptable excipient(s) selected from the group comprising water miscible
solvents, pro-penetrating agents, preservatives, antioxidants, chelating agents, surfactants
particularly liquid wetting surfactants, sunscreens, humectants, moisturizers, pH-adjusting agents,
colorants, fragrances, perfumes, or mixtures thereof.
According to another embodiment, the composition of the present invention comprises an
additional anti-acne agent.
According to another embodiment, the present invention relates to a method of treating acne
by administering stable topical aqueous composition having a pH of about 4 to about 6.5,
comprising:
(a) a therapeutically effective amount of adapalene;
(b) a therapeutically effective amount of benzoyl peroxide;
(c) one or more pharmaceutically acceptable excipient(s); and
(d) one or more gelling agent, wherein at least one of the gelling agent is a carbomer.
According to yet another embodiment, the composition comprises the other gelling agent(s)
selected from the group comprising cellulosic polymers such as hydroxypropyl cellulose,
hydroxyethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose; polyvinylalcohol;
natural and synthetic gums such as guar gum, hydroxypropyl guar gum, xanthan gum, acacia,
tragacanth; modified starch; acrylic acidfethyl acrylate copolymers; maleic anhydride-alkyl
methylvinylethers and copolymers; polymethacrylate copolymer; oleogels; trihydroxystearin;
aluminum magnesium hydroxy stearate; poloxamer; polyvinyl alcohol; methyl hydroxybenzoate;
ethyl hydroxybenzoate; propyl hydroxybenzoate; butyl hydroxybenzoate; polyacrylamide, or
mixtures thereof.
In another aspect, the present invention relates to a stable topical aqueous composition
having a pH of about 4 to about 6.5 comprising:
(a) a therapeutically effective amount of a retinoid or pharmaceutically acceptable salts thereof;
(b) a therapeutically effective amount of benzoyl peroxide;
(c) one or more pharmaceutically acceptable excipient(s); and
I (d) one or more gelling agent, wherein at least one of the gelling agent is a carbomer.
I I In another aspect, the present invention relates to a process for preparing topical aqueous
I
I
composition of adapalene and benzoyl peroxide, wherein the process comprises:
(a) dissolving all the excipients except the gelling agent in purified water to form an aqueous
phase;
(b) dispersing adapalene and benzoyl peroxide in separate portions of aqueous phase of step (a) and
mixing them to form the drug dispersion;
(c) dispersing the gelling agent in purified water;
6
(d) mixing the drug dispersion of step (b) with the gelling agent dispersion of step (c); and
(e) adjusting the pH to about 4 to about 6.5.
In another aspect, the present invention relates to a process for preparing topical aqueous
composition of adapalene and benzoyl peroxide, wherein the process comprises:
(a) dispersing gelling agent and one or more pharmaceutically acceptable excipient(s) in a part of
purified water under stirring to form a gelling phase;
(b) dispersing benzoyl peroxide and one or more pharmaceutically acceptable excipient(s) in a part
of purified water under stirring to get a uniform dispersion of benzoyl peroxide;
(c) dispersing adapalene and one or more pharmaceutically acceptable excipient(s) in another part
of purified water under stirring to get a uniform dispersion of adapalene;
(d) adding benzoyl peroxide dispersion obtained in step (b) to gelling phase obtained in step (a)
under stirring;
(e) adding adapalene dispersion obtained in step (c) to the final material obtained in step (d);
(f) adjusting the pH to about 4 to about 6.5; and
(g) finally adjusting the weight of the compostion to 100% with the remaining quantity of water.
Detailed Description of the Invention
The present invention provides a stable topical aqueous composition for the treatment of a
skin disorder, particularly acne. The stable topical composition having a pH of about 4 to about 6.5
comprises, a therapeutically effective amount of adapalene, a therapeutically effective amount of
benzoyl peroxide, one or more pharmaceutically acceptable excipient(s), and one or more gelling
agent, wherein at least one of the gelling agent is a carbomer.
The phrase "therapeutically effective amount" as used herein means that amount of a
compound which, when administered to a subject for treating a state, disorder, condition or causing
an action is sufficient to effect such treatment or action. The therapeutically effective amount will
vary depending on the compound, the disease and its severity and the age, weight, physical
condition and responsiveness of the mammal to be treated.
The term "adapalene" includes the base as well as salts formed with a pharmaceutically
acceptable base, in particular organic bases such as sodium hydroxide, potassium hydroxide and
aqueous ammonia, or organic bases such as lysine, arginine or N-methylglucamine. The term
"adapalene salts" also includes the salts formed with fatty amines such as dioctylamine and
stearylamine.
The composition of the present invention may comprise a retinoid other than adapalene. The
retinoid is selected from the natural or synthetic retinoid comprising tazarotene, retinoic acid,
tretinoin, isotretinoin, bexarotene, alitretinoin, vitamin A, retinol, retinal, retinyl palmitate, retinyl
7
e acetate, 6-(2-4,4-thiochroman-6-yl)-ethynyl)-3-pyridylmethanol2,- (2-(4,4-dimethyl thiochroman-
6-yl)-ethynyl)-5-pyridinecarboxaldehyde, ethyl 5-(2-(4,4-dimethylthiochroman-6-
yl)ethynyl)thiophene-2-carboxylate, or salts or derivatives thereof.
The topical aqueous composition of the present invention is present in a form of gel,
solution, foam, lotion or spray. More particularly, it is in the form of a gel.
The term "about", as used herein, when used along values assigned to certain measurements
and parameters means a variation of 10% from such values, or in case of a range of values, means a
10% variation from both the lower and upper limit of such ranges.
Adapalene is present in a concentration from about 0.001% to about 20% and benzoyl
peroxide is present in a concentration from about 0.001% to about 20% by weight of the
composition. More particularly, adapalene is present in a concentration from about 0.01% to about
10% and benzoyl peroxide is present in a concentration from about 0.01% to about 20% by weight
of the composition.
The term "gelling agent", as used herein, is synonymous with viscosifjring agent, solidifier,
thickening agent and refers to an agent that increases the viscosity of the formulation by forming a
crosslinking structure.
The gelling agent used in the present invention is a carbomer or a mixture of carbomer with
other gelling agent(s).
Generally, carbomers are high molecular weight water-soluble polymers of acrylic acid
cross-linked with ally1 ethers of sucrose and/or pentaerythritol. Carbomers have different viscosities
depending on their polymeric composition. Examples of carbomers for use herein include various
grades of ~arbo~olsu"c h as, for example, carbopolB 910, 934, 940, 94 1, 974, 980, 98 1, 1342,
5984, ETD2020, ETD 2050, and Ultrez 10 (available from Noveon of Cleveland, Ohio). Preferred
one is carbopolB 980 because it is a highly efficient thickener and it is ideal for formulating clear
aqueous and hydroalcoholic gels. Its benefits include short flow properties, high viscosity, high
suspending ability and high clarity.
Other gelling agent(s) which may be used in combination with carbomer include cellulosic
polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose,
hydroxypropylmethyl cellulose; polyvinylalcohol; natural and synthetic gums such as guar gum,
hydroxypropyl guar gum, xanthan gum, acacia, tragacanth; modified starch; acrylic acidethyl
acrylate copolymers; maleic anhydride-alkyl methylvinylethers and copolymers; polymethacrylate
copolymer; oleogels; trihydroxystearin; aluminum magnesium hydroxy stearate; poloxamer;
polyvinyl alcohol; methyl hydroxybenzoate; ethyl hydroxybenzoate; propyl hydroxybenzoate; butyl
hydroxybenzoate; polyacrylamide, or mixtures thereof.
The gelling agent is present in the composition at a concentration that provides sufficient
8
viscosity to the composition to allow the composition to adhere to the skin for a sufficient period of
time to allow the active ingredients to act on the affected areas. In some embodiments, two or more
gelling agents are used in combination. The gelling agent is present in a concentration of about
0.001% to about 30%, particularly in a concentration of about 0.01% to about lo%, more
particularly in a concentration of about 0.1% to about 5% by weight of the composition.
The pharmaceutical composition of the present invention can further include one or more
film- forming agents. The term "film-forming agent" means an ionic or nonionic hydrophilic
polymer having a molecular mass at least greater than 10,000; which during application to the skin
forms a continuous film. Examples of film-forming agents include, but are not limited to,
hydroxypropylmethylcellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
hydroxypropylcellulose, sodium carboxymethylcellulose, cellulose acetate,
hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers
such as Eudragito, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, or mixtures
thereof.
The pharmaceutical composition of the present invention can further include one or more
pharmaceutically acceptable excipient(s) selected from the group comprising water miscible
solvents, pro-penetrating agents, preservatives, antioxidants, chelating agents, surfactants
particularly liquid wetting surfactants, sunscreens, humectants, moisturizers, pH-adjusting agents,
colorants, fragrances, perfumes, or mixtures thereof.
Suitable examples of water miscible solvents include, but are not limited to, water, ethanol,
propylene glycol, glycerin, polyethylene glycol, or mixtures thereof.
The compositions of the invention may contain one or more pro-penetrating agents in
preferential concentrations ranging from about 0% to about 20% and more preferably ranging from
about 2% to about 6% by weight, relative to the total weight of the composition. They should
generally not dissolve the active agents at the percentage used, should not cause any
exothermic reactions harmful to benzoyl peroxide, should aid in the satisfactory dispersion of the
active agents, and should have antifoaming properties. Suitable pro-penetrating agents are
selected from the group comprising of propylene glycol, dipropylene glycol, propylene glycol
dipelargonate, lauroglycol, ethoxydiglycol, or mixtures thereof.
The composition of the present invention may comprise about 0% to about 2.0% by weight
of preservatives by total weight of the composition. Examples of preservatives include, but are not
limited to, methyl, ethyl, propyl and butyl esters of hydroxy benzoic acid, benzoic acid,
chlorhexedine, benzalkonium chloride, 2-phenoxyethanol, cetrimide, potassium sorbate, thiomersal,
or mixtures thereof.
As the active ingredients are more susceptible to oxidation in an aqueous medium,
9
a therefore, an antioxidant is used in the composition to retard oxidation and deterioration of the
active ingredients, thus providing the composition with long-term stability. Specific examples of
antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), sodium metabisulfite, ascorbic acid, ascorbyl palmitate, thiourea,
acetylcysteine, dithiothreitol, cysteine hydrochloride, propyl gallate, tocopherol, or mixtures
thereof. Particularly, the antioxidant is butylated hydroxytoluene (BHT). Antioxidants may be
present in an amount of about 0% to about 0.3 % by weight of the composition.
Examples of chelating agents include, but are not limited to, edetate salts for example
edetate disodium and citric acid. Chelating agents chelate metal ions present in the composition that
may be detrimental to the shelf life of the formulation. Particularly the chelating agent is present in
an amount of about 0.01% to about 0.5 % by weight of the
composition.
A surfactant may also be included in the formulation of the present invention to allow good
dispersion of the active ingredients. Examples of surfactants include, but are not limited to,
polyethoxylated fatty acid esters, polyoxyethylene sorbitan esters, polyoxyethylene hydrogenated
castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan esters, sodium lauryl sulphate,
docusate sodium, nonooxynol, glyceryl monostearate, or mixtures thereof. Particularly the liquid
wetting surfactants used in the present invention include compounds of the poloxamer family and
more particularly poloxamer 124 and poloxamer 182.
The pharmaceutical composition of the present invention may also include one or more pHadjusting
agents. Examples of pH-adjusting agents include, but are not limited to, pharmaceutically
acceptable organic or inorganic acids or bases; for example sodium hydroxide, tromethamine,
hydrochloric acid, or mixtures thereof. Particularly the compositions of the present invention have a
pH of about 4 to about 6.5.
Examples of humectants include, but are not limited to, glycerol, sorbitol.
Examples of fragrances and perfumes include, but are not limited to, lavender oil, rose oil,
lemon oil, almond oil.
The present invention relates to a process of preparing stable topical aqueous composition
of adapalene and benzoyl peroxide, wherein the process comprises:
(a) dissolving all the excipients except the gelling agent in purified water to form an aqueous
phase;
(b) dispersing adapalene and benzoyl peroxide in separate portions of aqueous phase of step (a) and
mixing them to form the drug dispersion;
(c) dispersing the gelling agent in purified water;
(d) mixing the drug dispersion of step (b) with the gelling agent dispersion of step (c); and
10
0 (e) adjusting the pH to about 4 to about 6.5.
The present invention also relates to a process of preparing the stable topical aqueous
composition of adapalene and benzoyl peroxide, wherein the process comprises:
(a) dispersing gelling agent and one or more pharmaceutically acceptable excipient(s) in a part of
purified water under stirring to form a gelling phase;
(b) dispersing benzoyl peroxide and one or more pharmaceutically acceptable excipient(s) in a part
of purified water under stirring to get a uniform dispersion of benzoyl peroxide;
(c) dispersing adapalene and one or more pharmaceutically acceptable excipient(s) in another part
of purified water under stirring to get a uniform dispersion of adapalene;
(d) adding benzoyl peroxide dispersion obtained in step (b) to gelling phase obtained in step (a)
under stirring;
(e) adding adapalene dispersion obtained in step (c) to the final material obtained in step (d);
(f) adjusting the pH to about 4 to about 6.5; and
(g) finally adjusting the weight of the compostion to 100% with remaining quantity of water.
The present invention also relates to a method for treating acne by administering the
composition of the present invention to an affected area of the subject's skin having such disorder in
an amount and for a period of time sufficient to improve the skin disorder.
The composition of the present invention may further include an additional antiacne agent.
Examples of additional anti-acne agents include, but are not limited to, an antibiotic, salicylic acid,
azelaic acid, retinoids other than adapalene, metronidazole, or mixtures thereof.
The present invention is illustrated below by reference to the following examples. However,
one skilled in the art will appreciate that the specific methods and results discussed are merely
illustrative of the invention, and not to be construed as limiting the invention.
EXAMPLES
Example 1 :
Manufacturing Process:
(1) Preparation of aqueous phase
(a) A part of purified water was taken in main manufacturing vessel; and disodium edetate
was added under stirring to dissolve.
(b) Propylene glycol was added to step (a) and mixed under stirring.
(c) Sodium docusate was dissolved in glycerin.
(d) Step (c) material was added to step (b) and mixed under stirring.
(e) Poloxamer 124 was added to step (d) material and mixed under stirring.
(2) Preparation of d r u ~di spersion
(a) Benzoyl peroxide was added to a portion of aqueous phase and homogenized to get a
uniform dispersion.
(b) Adapalene was added to another portion of aqueous phase and mixed under stirring
(c) Step (a) material was added to step (b) material and mixed under stirring.
(3) Addition of gelling agents
Carbomer was added to a portion of purified water and mixed under stirring.
(4) Preparation of gel
The drug dispersion of step (2) was mixed with the gelling agent dispersion of step (3). The
pH was checked and adjusted to S0.5 with sodium hydroxide solution. The weight was adjusted to
100% with remaining quantity of water.
Table 1 shows physical properties of the gel composition prepared according to Example 1
after storage under normal and accelerated conditions.
Table 1 :
* Not checked
Example 2:
Manufacturing Process:
49 days
37,800
4.90
25,200
4.77
S.No.
1
2
3
4
5
6
7
8
9
10
11
(1) Preparation of gelling phase
(a) Disodium edetate was dissolved in a part of purified water.
13
62 days
46,000
4.95
22,400
4.67
20 days
36,400
5.07
33,000
4.85
34 days
46,000
4.95
30,000
4.82
7 days
39,200
*
36,000
*
Initial
40,200
5.05
40,200
5.05
Ingredients
Adapalene
Benzoyl peroxide
Propylene glycol
Poloxamer 124
Disodium edetate
Glycerin
Docusate sodium
Carbop01980
Hydroxypropyl cellulose
Sodium hydroxide
Purified water
10 days
40,000
4.83
33,600
4.70
Parameters
Viscosity
PH
Viscosity
PH
S.No.
1
2
Percent (%)
weight by weight
0.10
2.50
4.00
0.20
0.10
4.00
0.05
1.25
0.40
qs to pH 5
qs to 100
Storage
Condition
25"C/60%RH
40°C/75%RH
(b) Carbopol980 was added to step (a) and mixed under stirring.
(2) Preparation of benzoyl peroxide dispersion
(a) A part of purified water was taken and hydroxypropyl cellulose was added and mixed
under stirring.
(b) Benzoyl peroxide was added to step (a) material and mixed under stirring and
homogenized to get a uniform dispersion.
(3) Preparation of adapalene dispersion
(a) A part of purified water was taken and propylene glycol, glycerin, poloxamer and
disodium docusate was added and mixed under stirring.
(b) Adapalene was added to step (a) material and mixed under stirring and homogenized to
get a uniform dispersion.
(4) Preparation of gel
(a) Step (2) material was added to step (1) material under stirring.
(b) Step (3) material was added to step (a) material under stirring.
(c) The pH was checked and adjusted to 5*0.5 with sodium hydroxide solution. The weight
was adjusted to 100% with remaining quantity of water.
Table 2 shows physical properties of the gel composition prepared according to Example 2
after storage under accelerated conditions.
Table 2:
While several particular forms of the invention have been illustrated and described, it will
be apparent that various modifications and combinations of the invention detailed in the text can be
made without departing from the spirit and scope of the invention.
3 months
32,600
4.55
2 months
39,000
4.65
Initial
5 3,600
5.08
Storage Condition
40°C/75%RH
Parameters
Viscosity
PH
WE CLAIM:
1. A stable topical aqueous composition having a pH of about 4 to about 6.5 comprising;
(a) a therapeutically effective amount of adapalene;
(b) a therapeutically effective amount of benzoyl peroxide;
(c) one or more pharmaceutically acceptable excipient(s); and
(d) one or more gelling agent, wherein at least one of the gelling agent is a carbomer.
2. The stable topical aqueous composition according to claim 1, is in the form of a gel,
solution, foam, lotion or spray.
3. The stable topical aqueous composition according to claim 1, wherein adapalene is present
in a concentration from about 0.001% to about 20% by weight of the composition and
benzoyl peroxide is present in a concentration from about 0.001% to about 20% by weight
of the composition.
4. The stable topical aqueous composition according to claim 1, wherein adapalene is present
in a concentration from about 0.01 % to about 10% by weight of the composition and
benzoyl peroxide is present in a concentration from about 0.01 % to about 20% by weight of
the composition.
5. The stable topical aqueous composition according to claim 1, wherein the gelling agent is
present in a concentration of about 0.001% to about 30% by weight of the composition.
6. The stable topical aqueous composition according to claim 5, wherein the gelling agent is
present in a concentration of about 0.1 % to about 5% by weight of the composition.
7. The stable topical aqueous composition according to claim 1, wherein the pharmaceutically
acceptable excipient(s) are selected from the group comprising water miscible solvents, propenetrating
agents, preservatives, antioxidants, chelating agents, surfactants particularly
liquid wetting surfactants, sunscreens, humectants, moisturizers, pH-adjusting agents,
colorants, fragrances, perfumes, or mixtures thereof.
8. The stable topical aqueous composition according to claim 1, comprises other gelling
agent(s) selected from the group comprising cellulosic polymers such as hydroxypropyl
cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose;
15
polyvinylalcohol; polyquaternium-10; natural and synthetic gums such as guar gum,
hydroxypropyl guar gum, xanthan gum, acacia, tragacanth; modified starch; acrylic
acid/ethyl acrylate copolymers; maleic anhydride-alkyl methylvinylethers and copolymers;
polymethacrylate copolymer; oleogels; trihydroxystearin; aluminum magnesium hydroxy
stearate; poloxamer; polyvinyl alcohol; methyl hydroxybenzoate; ethyl hydroxybenzoate;
propyl hydroxybenzoate; butyl hydroxybenzoate; polyacrylamide, or mixtures thereof.
9. A process for the preparation of the stable topical aqueous compositing, wherein the said
process comprises the steps of:
(a) dispersing gelling agent and one or more pharmaceutically acceptable excipient(s) in
a part of purified water under stirring to form a gelling phase;
(b) dispersing benzoyl peroxide and one or more pharmaceutically acceptable
excipient(s) in a part of purified water under stirring to get a uniform dispersion of
benzoyl peroxide;
(c) dispersing adapalene and one or more pharmaceutically acceptable excipient(s) in
another part of purified water under stirring to get a uniform dispersion of
adapalene;
(d) adding benzoyl peroxide dispersion obtained in step (b) to gelling phase obtained in
step (a) under stirring;
(e) adding adapalene dispersion obtained in step (c) to the final material obtained in step
(d);
( f ) adjusting the pH to about 4 to about 6.5; and
(g) finally adjusting the weight of the compostion to 100% with remaining quantity of
water.
10. The stable topical aqueous composition as described and illustrated in the examples herein.