FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"A NOVEL PROCESS TO FORMULATE A STABLE TOPICAL DRUG
DELIVERY SYSTEM CONTAINING IMIQUIMOD"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION: AND THE MANNER IN,
WHICH IT IS TO BE PERFORME


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A NOVEL PROCESS TO FORMULATE A STABLE TOPICAL DRUG DELIVERY
SYSTEM CONTAINING IMIQUIMOD
FIELD OF THE INVENTION
This invention relates to a novel process to formulate a stable topical pharmaceutical
composition containing Imiquimod.
BACKGROUND OF THE INVENTION
Imiquimod, chemically known as l-(2-Methylpropyl)-l H -imidazo[4,5- c ]quinolin-4-
amine, may be represented by the structure of Formula I.

Imiquimod is an immune response modifier and its mechanism of action is believed to be
secondary to local cytokine induction in the skin. In animal models imiquimod is an
effective antiviral and antitumour agent. Imiquimod is not & nucleoside analogue and its
activity is principally due to induction of alpha interferon but other cytokines are also
involved. Saturable binding studies suggest a membrane receptor for imiquimod exists on
responding cells. Binding kinetics indicate a high and low affinity binding site. When
imiquimod cream is applied topically to the back of mice, mRNA for alpha interferon and
increased protein levels of interferon and tumour necrosis factor alpha are detected in the
skin.
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The mechanism of action of Imiquimod cream in treating superficial basal cell carcinoma
(sBCC) lesions is unknown. However, clinical observations are consistent with a mechanism
of action that involves the stimulation of a local immune-mediated response at the site of
application that is similar to classic cell-mediated immune reactions in the skin. Two clinical
studies have shown that Imiquimod stimulates the infiltration of tumour-destructive cells (T-
cell lymphocytes, dendritic cells and macrophages) into the basal cell carcinoma lesion and
reduces the defence mechanisms of the tumour.
US 5238944, Riker Laboratories, Inc. (St. Paul, MN), filled in March 3, 1992, herein
incorporated by reference, discloses an Pharmaceutical formulations and adhesive-coated
sheet materials for the topical and/or transdermal delivery of Imiquimod along with a
pharmaceutically acceptable vehicle for said l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine,
which vehicle comprises isostearic acid in an amount of about 3 percent to about 45 percent
by weight based on the total weight of said formulation, said formulation being further
characterized in that, when tested according to the hairless mouse skin model the
formulation provides a penetration of the agent of at least about 10 percent of the total
amount of the agent contained in the formulation in 24 hours. The present invention
disclosed herein in this specification is using Imiquimod with Lenoleic acid with
combination of anti oxidants and/or lactic acid optionally with or without anti oxidants. Use
of linoleic acid with antioxidants not only imparts good stability to the composition, but also
imparts good texture to the composition which remains stable for longer period of time and
gives good spreadability.
WO2003045391 Al, of 3M INNOVATIVE PROPERTIES CO US, Claims Imiquimod as a
pharmaceutical formulation comprising: an immune response modifier (IRM), along with a
fatty acid; a hydrophobic, aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms; and a hydrophilic viscosity enhancing agent
selected from cellulose ethers and carbomers.The invention disclosed herein in this
specification does not contain any cellulose ethers and carbomers as Viscolizing agent but
discloses xanthan gum in the composition as viscosity enhancing agent Also this patent
discloses a combination of anti oxidants e.g. Butylated hydroxytolune, Butylated
hydroxyanisole. The addition of combination of anti oxidants prevents the oxidation of
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oxidation susceptible fatty acids . Thus the oxidative degradation of the fatty acid is
controlled using Butylated hydroxytolune, Butylated hydroxyanisole alone or in
combination in this invention . The cold process of manufacturing Imiquimod cream is also
disclosed in this specification. The advantage of this process is due to no contact with heat
during the process of manufacturing , the oxidative degradation of the product is minimized
and thus the process results into a stable product.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, is to provide a process for
formulating a stable topical pharmaceutical composition of Imiquimod.
Yet another aspect of the invention is to provide a process that results into a stable topical
composition of Imiquimod.
Yet another aspect of the invention is to provide a Hot melt process for making the topical
application of Imiquimod.
Further aspect of the invention is to provide a cold process for making a stable composition
of topical application of Imiquimod.
Further aspect of the invention is to use an antioxidants alone or in combination to process a
stable composition of topical application of Imiquimod.
Yet another aspect of the invention is when linoleic acid is used in the composition and the
process of manufacture is hot/cold melt process Butylated hydroxytolune, Butylated
hydroxyanisole in combination are essential elements in the desired concentration to have a
stable composition. In such case use of preservatives like Methyl parahydraxybenzoate and
propyl parahydraxybenzoate are optional.
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Yet another aspect of the invention is when lactic acid is used in the composition and the
process of manufacture is hot/cold melt process Butylated hydroxytolune, Butylated
hydroxyanisole in alone/in combination are optinal in the desires concentration to have a
stable composition.
In accordance with a another embodiment of the present invention, a process for preparing a
stable pharmaceutical formulation is provided, the process comprising (a) preparing a
solution comprising a therapeutically effective amount of imiquimod or a pharmaceutically
acceptable salt thereof and an effective amount of linoleic acid, lactic acid and mixtures
thereof; (b) preparing a wax phase under heating; and adding an aqueous phase to the
solution and wax phase, either simultaneously or sequentially.
Yet another aspect of the invention is to disclose a process that results into a pharmaceutical
composition in the form of topical application that is non-irritant to the skin on local
application.
Further aspect of the invention is to provide a process to formulate a topical , stable ,
pharmaceutical composition using Linoleic acid or lactic acid or combination thereof.
A pharmaceutical formulation of the invention can be in the form of cream for local
application to deliver the therapeutically effective amount of active pharmaceutical
ingredient.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention discloses a process of manufacturing a stable pharmaceutical
formulations such as cream that contain 1-isobutyl-lH-imidazo[4,5-c]-quinolin-4-amine and
a fatty acid such as Linoleic acid and/or lactic acid. The formulations of the invention
provide desirable skin penetrability of the 1-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine.
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The compound l-isobutyl-IH-imidazo[4,5-c]-quinolin-4-amine is a known antiviral agent
that is also known to induce interferon biosynthesis. Furthermore, the fact that the
compound is an interferon inducer suggests that it, and therefore formulations containing it,
might be useful in the treatment of numerous other diseases, such as rheumatoid arthritis,
warts, eczema, hepatitis B, psoriasis, multiple sclerosis, essential thrombocythaemia, and
cancer, such as basal cell carcinoma and other neoplastic diseases. The amount of 1-
isobutyl-1 H-imidazo[4;5-c]quinolin-4-arnine present in a formulation of the invention will
be an amount effective to treat the targeted disease state to prevent the recurrence of such a
disease or to promote immunity against such a disease. The amount is preferably about 0.5
percent to about 9 percent by weight based on the total weight of a formulation.
A fatty acid such as Linoleic acid, lactic acid and/or a mixture thereof is incorporated into a
formulation of the invention.
A cream according to the invention contains l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine
and fatty acid.
The amount of l-isobutyl-lH-imidazo[4,5-c]-quinolin-4-amine present in a cream is
preferably about 0.1 percent to about Spercent by weight, and more preferably about 1
percent to about 7 percent by weight, based on the total weight of the cream.
The total amount of fatty acid present in a cream of the invention is preferably about 5
percent to about 40 percent by weight, and more preferably about 20 percent to about 30
percent by weight, based on the total weight of the cream.
Optionally, a cream of the invention can contain emollients, emulsifiers, thickeners, and/or
preservatives.
Emollients such as long chain alcohols, e.g., cetyl alcohol, stearyl alcohol and cetearyl
alcohol; hydrocarbons such as petrolatum and light mineral oil; or acetylated lanolin can be
included in a cream of the invention. A cream can contain one or more of these emollients
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either alone or in combination thereof and other material known to those of ordinary skill in
the art.
Emulsifiers such as nonionic surface active agents, e.g., polysorbate 60 , sorbitan
monostearate, polyglyceryl-4 oleate, and polyoxyethylene(4)lauryl ether or trivalent cationic
a cream of the invention. A cream can contain one or more emulsifiers alone or in
combinations thereof and other material known to those of ordinary skill in the art.
Pharmaceutically acceptable thickeners, such as Xanthan Gum and long chain alcohols (i.e.
cetyl alcohol, stearyl alcohol or cetearyl alcohol) can be used. A cream can contain one or
more thickeners alone or in combination and the other thickeners known to the person
skilled in the art.
Preservatives such as methylparaben, propylparaben and benzyl alcohol can be present in a
cream of the invention. The appropriate amount of such preservative(s) alone or in
combination or any other preservatives that is known to the person skilled in the art.
Anti Oxidants such as Butylated hydroxytolune, Butylated hydroxytolune, Butylated
hydroxyanisole in combination are used in case of linoleic acid in the composition and
method of manufacturing is cold /hot process. In case of lactic acid having process of
manufacturing as cold /hot process the use of anti oxidants is optional. This may include the
anti oxidants that are known to the person skilled in the art.
Optionally, an additional solubilizing agent such as benzyl alcohol, lactic acid, acetic acid,
stearic acid or hydrochloric acid can be included in a cream of the invention. They can be
used alone or in combination and may also include other solubilizing agents that are known
to the person skilled in the art.
Optionally, a cream of the invention can contain a humectant such as glycerin, skin
penetration enhancers such as butyl stearate, and additional solubilizing agents.
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It is known to those skilled in the art that a single ingredient can perform more than one
function in a cream, i.e., cetyl alcohol can serve both as an emollient and as a thickener.
Generally, a cream consists of an oil phase and a water phase mixed together to form an
emulsion. Preferably, the amount of water present in a cream of the invention is about 30
percent to about 75 percent by weight based on the total weight of the cream.
The examples mentioned below demonstrate some illustrative synthetic procedures for
preparing the pharmaceutical compositions described herein. The examples are provided to
illustrate particular aspect of the disclosure and do not limit the scope of the present
invention as defined by the disclosure.
Following are two proposed formulae and brief manufacturing procedure for Imiquimod
Cream 5.0%
EXAMPLE 1.
HOT PROCESS

S.No. Composition %w/w
1. Imiquimod 5.00
2. Linoleic acid 25.0
3. Benzyl alcohol 2.00
4. Cetyl alcohol 2.20
5. Stearyl alcohol 3.10
6. White soft paraffin 3.00
7. Polysorbate 60 3.40
8. Sorbitan monostearate 0.60
9. Glycerine 2.00
10. Methyl parahydraxybenzoate 0.20
11. Propyl parahydroxybenzoate 0.02
12. Butylated hydroxytolune 0.05-0.15
13. Butylated hydroxyanisole 0.05-0.15
14. Xanthan Gum 0.10
15. Purified Water q. s. to 100
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Brief Manufacturing Procedure
Drug solution
Added benzyl alcohol to Imoleic acid and mixed well. Added drug under stirring and stirred
until it dissolves completely. Ensured complete drug dissolution. (Heat if necessary)
Wax phase
Melted white soft paraffin, cetyl alcohol, stearyl alcohol, polysorbate 60 sorbitan
monostearate and maintained the temperature at 65 °C-70°C,
Add and dissolve Butylated hydroxytolune, Butylated hydrox yam sole.
Final oil phase
Added wax phase to drug solution and maintained the temperature at 65 °C-70°C.
Aqueous phase
Dispersed xanthan gum in glycerine and added water containing dissolved methyl paraben
and propyl paraben, hydrated for 1 hour. Heated and maintained temperature at 65 °C-70°C.
E nullification
Added aqueous phase to oil phase slowly and homogenized for 15 minutes.
Cooling
Allowed to cool under slow stirring.
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EXAMPLE 2.
COLD PROCESS

S.No. Composition %w/w
1. Imiquimod 5.00
2. Linoleic acid 25.0
3. Benzyl alcohol 2.00
4. Emulium delta 2-5
5. Labrafac lipophile WL1349 3-6
6. Polysorbate 60 3.00
7. Glycerin 2.00
8. Methyl parahydraxybenzoate 0.20
9. Propyl parahydroxybenzoate 0.02
10. Butylated hydroxytolune 0.05-0.15
11. Butylated hydroxyanisole 0.05-0.15
12. Xanthan Gum 0.05-0.5
13. Purified Water q.s. to 100
Brief Manufacturing Procedure
Drug solution
Added benzyl alcohol to linoleic acid and mixed well. Added drug under stirring and stirred
until it dissolves completely. Ensured complete drug dissolution.
Wax phase
Melted emulium delta and added labrafac lipophile to it.
Final oil phase
Added wax phase to drug solution and mixed well.
Aqueous phase
Dispersed xanthan gum in glycerine and added water containing dissolved methyl paraben
and propyl paraben, hydrated for 1 hour.
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Emulsification
Added aqueous phase to oil phase slowly and homogenized for 15 minutes.
Final stirring
After completion of homogenization allowed to stir for 15 minutes.
EXAMPLE 3.
COLD PROCESS

S.No. Composition %w/w
16. Imiquimod 5.00
17. Lactic acid 15-25
18. Arlasolve DMI (Dimethyl isosorbide) 2-3
19. Propylene glycol stearate (55% monoester) 8.00
20. Stearyl alcohol & Ceteareth-20
(Ptomulgen.- G) 7.00
21. Titanium dioxide 1.00
22. Aluminum starch octenylsuccinate
(gamma irradiated) 10.00
23. White wax 05.00
24. White petrolatum 36.0-47.0
Note: May contain benzyl aJcohoi.
Brief Manufacturing Procedure
Drug solution
Add drug in lactic acid under stirring. Heat it upto 50-60°C and dissolve under stirring. Add
arlasolve DMI and mix well. Maintain temperature of this phase to 65°C - 70°C.
Oil phase
Melted white wax, propylene glycol stearate (55% monoester), stearyl alcohol & ceteareth-
20 (Promulgen- G), white petrolatum, and maintained the temperature of oil phase at 65 °C-
70°C.
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Mixing
Added drug solution to oil phase (both phases maintained at 65 °C-70°C) and mixed to
achieve adequate emulsification. Added titanium dioxide and continue homogenization for
15 minutes. Coo it to 40-45° C and add aluminium starch octenyl succinate under stirring at
and mixed for 10 minutes.
Cooling
Cooled under stirring to room temperature.
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Claims:
1. A process for preparing a stable pharmaceutical formulation, the process
comprising (a) preparing a solution comprising a therapeutically effective amount of
imiquimod or a pharmaceutical ly acceptable salt thereof and an effective amount of a
linoleic acid, lactic acid or mixtures thereof; and (b) adding this solution to an oil phase.
2. A process for preparing a stable pharmaceutical formulation, the process
comprising (a) preparing a solution comprising a therapeutic ally effective amount of
imiquimod or a pharmaceutically acceptable salt thereof and an effective amount of a
compound selected from linoleic acid, lactic acid or mixtures thereof; (b) preparing a wax
phase under heating; and adding aqueous phase to oil aqueous phase for emulsification ,
either simultaneously or sequentially.
3. The composition as claimed in claim 1, wherein the composition further
comprises one or more additional ingredients selected from the group consisting of cosmetic
agents, pharmaceutical agents, topical agents, and mixtures and combinations thereof.

4. The process of claim 1 and 2. wherein the stable pharmaceutical formulation is in
the form of a solution, a get, a lotion, a cream, an ointment, a shampoo, a spray, a stick, a
powder, etc.
5. The process of claim 1-2. wherein the imiquimod is present in an amount of about
0.1 weight percent to about 9 weight percent, based on the total weight of the formulation.
6. The process of features 1-2, wherein the imiquimod is present in an amount of
about 0.5 weight percent to about 8 weight percent, based on the total weight of the
formulation.
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7. The process of features 1-6, wherein lactic acid, linoleic acid or mixture thereof is
present in an amount of about 5 weight percent to about 40 weight percent, based on the
total weight of the formulation.
8. The process of features 1-8, wherein the linoleic acid, lactic acid or mixture
thereof is present in an amount of about 15 weight percent to about 30 weight percent, based
on the total weight of the formulation.
9. The process of features 1-8, further comprising adding an antioxidant selected
from the group consisting of butylated hydroxytolune, butylated hydroxyanisole and
mixtures thereof.
10. A stable pharmaceutical formulation comprising (a) a therapeutically effective
amount of imiquimod or a pharmaceutically acceptable salt thereof; (b) an agent selected
from linoleic acid, lactic acid or mixtures thereof; and (b) a pharmaceutically acceptable
vehicle for the imiquimod.
Dated this twenty-first (21st) day of November, 2006

Taranpreet Lamba.
(Dy.General Manager -IPM )
Glenmark Pharmaceuticals Limited
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