FORM2
THE PATENT ACT 1970
(39 of 1970)
& -
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 arid rule13)
1. TITLE OF THE INVENTION: "Topical Foam"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field :
The present invention relates to a stable topical foam preparation comprising a steroid and
a keratolytic agent, its manufacturing process and, use thereof.
Background and prior art:
Psoriasis is an inflammatory skin disorder that affects 1 to 3 percent of population throughout the world. The scalp is a favored site for psoriasis and sometimes may be the only site affected. Psoriasis involves the scalp approximately 50% of the time. Similarly seborrhoeic dermatitis has a prevalence of 1 to 3% of the general population and scalp is a common site.
Scalp psoriasis is a frequent expression of the common skin disease psoriasis, scaling and itching are the two major complaints. Topical treatments are the mainstay of the treatment of psoriasis of the scalp. The vehicles as well as the active ingredient are relevant to the efficacy, tolerability and compliance of the preparation. Vehicles can be shampoos, lotions, gels, foams, creams and more greasy ointments. Various active ingredients like keratolyses, coal tar, dithranol, corticosteroids and vitamin D3 analogues are used but topical corticosteroids remain the most popular treatment of scalp psoriasis. The several corticosteroids that have been used for the treatment of scalp psoriasis are alclometasone dipropionate, amcinonide, beclamethasone dipropionate, betamethiasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, flumethasone pivalate, fluclprolone acetonide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone preparations, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate, triamcinolone acetonide, and pharmacologically effective mixtures thereof.
US 6,126,920 claims a method of treating skin diseases by employing a pharmaceutical foaming composition comprising of beclomethasone valerate as the corticosteroid used in amounts of 0.01 to 1.0% w/w. The preparation further comprises of an aliphatic alcohol, water, fatty alcohol, a surface-active agent, a propellant and a buffering agent. The patent
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also claims that the formulation can be used for the" treatment of skin diseases inter alia scalp psoriasis. -
However, it is seen that betamethasone alone is not very effective in treating the above-mentioned condition. Since the skin structure of the scalp in psoriasis is highly squamous in nature, betamethasone cannot penetrate easily through the thick squamous layer.
Therefore, the therapeutic efficacy of the drug decreases. To counter this problem,
i keratolytic agents such as salicylic acid & its derivatives have been combined along with
the corticosteroids. These keratolytic agents desquamate the' scalp region and thereby
enhancing penetration of the corticosteroid.
Several preparations comprising the said combination of corticosteroid and keratolytic agents have been known.
FR2366840 claims a combination of a corticosteroid such as betamethasone or neomycin along with salicylic acid in form of a cream or an ointment.
RU2223765 discloses a combination of betamethasone and salicylic acid in Vaseline oil and Vaseline as accessory substances.
US5505949 claims a cream formulation of clotrimazole, betamethasone and salicylic acid composition.
However, due to the undesirable consistency of these hydrophobic carriers, their use is limited. For instance, ointments containing white petrolatum, e. g., Vaseline petroleum jelly, as the carrier often form an impermeable barrier, so that metabolic products and excreta from the wounds to which they are applied are not easily removed or drained away. Furthermore, it is difficult for the active drug dissolved in the carrier to pass through the white petrolatum barrier layer into the wound tissue, so the efficacy of the drug is reduced.
In addition, ointments and creams often do not create an environment for promoting respiration of the wound tissue and it is not favorable to the normal respiration of the skin.
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Their main disadvantage is in their sticky feeling; which remains so long after treatment is over. This decreases the patient compliance drastically. Therefore there is a strong need for providing a topical formulation that omits all the disadvantages of the above mentioned pharmaceutical preparations and yet retains the beneficial therapeutic properties of the drug combination.
WO2004037225 relates to an alcohol -free cosmetic or pharmaceutical foam carrier comprising water, a hydrophobic solvent, a foam adjuvant agent, a surface-active agent and a water gelling agent.
US Pat. 6,423, 323 describes an aqueous foam emulsion. The composition includes a hydrophobic phase including fatty acids, emulsifiers and co-emulsifiers, and an aqueous phase containing hydrophilic moisturizers and emulsifiers.
1331 /MUM/2004 relates to water-based topical foam comprising a corticosteroid and keratolytic agent as quick break foam.
It has been observed that the problem with these water-based foams is that they are not stable over the shelf Life, if they contain water insoluble drugs and unstable drugs, in particular it has been observed that the keratolytic agent is not very stable in water based foams.
There is therefore a need to provide stable foam compositions comprising water insoluble drugs and unstable drugs.
Object of the invention:
The object of the present invention is to provide a stable topical pharmaceutical foam formulation comprising a steroid and a keratolytic agent.
Another object of the present invention is to provide a stable topical pharmaceutical foam composition comprising steroid and keratolytic agent , wherein the keratolytic agent is stable throughout the shelf life.
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It is yet another object of the present invention to provide a stable topical pharmaceutical foam composition for the treatment of skin and its related disorders such as eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrheic dermatitis, neurodermatitis, psoriasis and intertrigo.
It is yet another object of the present invention to provide for a method of manufacturing the said stable topical pharmaceutical foam composition.
Summary of the Invention:
In one aspect, the present invention provides a stable topical pharmaceutical foam composition comprising a steroid and a keratolytic agent.
In another aspect, the present invention provides a stable topical pharmaceutical foam composition comprising betamethasone valerate and salicylic acid.
The present invention further provides a process for manufacturing a stable topical pharmaceutical foam composition.
In another aspect, the invention provides the method of treating a patient with psoriasis, eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrheic dermatitis, neurodermatitis, psoriasis and intertrigo, which method comprises administering to patient in need thereof a stable topical pharmaceutical foam composition according to the present invention.
Detailed description of the invention :
As discussed in the prior art it has been observed that the insoluble drugs or unstable drugs are not very stable throughout the shelf life as aqueous foams are, and in particular it has been observed that keratolytic agents are unstable in aqueous foam compositions. Hence there is a need to develop a stable foam composition.
Therefore, the present inventors have developed a stable topical composition comprising keratolytic agent in combination with steroid in waterless foam and studied the stability of the composition and found that the composition remains stable throughout the shelf
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life. Further the inventors have found that the use of waterless foams ;make it easy to incorporate water insoluble or unstable drugs.
Betamethasone is a synthetic medium potency, corticosteroid for topical dermatological use. It has anti-inflammatory, anti-pruritic and vasoconstrictive properties. The mechanism of anti-inflammatory activity of topical steroids, in general is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins. Phospholipase A2 is responsible for release of arachidonic acid from membrane phospholipids. Potent mediators of inflammation like prostaglandins and leukotrienes are synthesized from arachidonic acid. By inhibiting release of arachidonic acid, topical corticosteroids can control biosynthesis of inflammatory mediators and thus local inflammation.
Other corticosteroids that may be used for treatment of psoriasis include one or more of but not limited to alclometasone dipropionate, amcinonide, beclamethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, flumethasone pivalate, fluclorolone acetonide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone preparations, ' fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate. triamcinolone acetonide, and pharmacologically effective mixtures thereof. In the addition to the above mentioned drugs, the various other salts, solvates, prodrugs, derivatives,esters,-polymorphs or enantiomers of the specific drugs mentioned above and other corticosteroids are to be considered to be covered within the scope of this invention.
The preferred corticosteroids according to the present' nvention are betamethasone and clobetasol
The betamethasone may preferably be used in its salt/ester form such as valerate, hydrochloride, phosphate, salicylate, sodium phosphate, valero acetate, dipropionate, etc. The preferred salt form is betamethasone valerate. The clobetasol may preferably be selected from its salts, solvates, prodrugs, derivatives, esters, polymorphs or enantiomers thereof. The preferred salt/ester of clobetasol is clobetasol propionate.
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The corticosteroid may be used in the concentration of 0.025% to 0.1% as topical application.
Salicylic acid is 2-hydroxybenzoic acid which is used as keratolytic(assists in desquamation), bacteriostatic and fungistatic agent in topical applications. Its main clinical use is as a keratolytic and an agent that increases percutaneous absorption of combined drugs by, removing the stratum corneum. The keratolytic activity results from solubilization of inter cellular ground substance in the stratum corneum and shedding of the scales which are bound by it. In psoriasis, salicylic acid appears to enhance desquamation and removes abnormal scale and is, also, used in combination with anthralin, tar and corticosteroids to enhance penetration of the active drug.
Several other keratolytic agents which are also anti-inflammatory in nature that may be used . They may be selected from but not limited to alpha-hydroxy acids, such as lactic acid and glycolic acid and their respective salts and derivatives; and beta-hydroxy acids, urea, benzoyl peroxides & related compounds, benzoyl benzoates & related esters. The keratolyses may be used in the concentration of 2 % to 10% for hyperkeratotic and sealing skin conditions, most preferably in a range of 2% to 5% usually in conjunction with other drugs.
The topical pharmaceutical foam formulation of the present invention has further advantages over other pharmaceutical preparations such as creams, ointments, lotions or liquid preparations. Mousses and foams use a propellant (pressurized gas) and a surfactant in addition to the drug to help create smooth, creamy foam. The liquid propellant then quickly evaporates, creating foam. The mousse foam makes it easy to apply the drug to your hair because in the foaming state it can be spread very thinly to the entire area of the scalp.
Another benefit of mousse is that its foamy state is not runny and thus will stay where you put it. Another advantage of mousse is that its application provides a larger surface area being less viscous, hence better activity. Therefore, overall mousse and foams form achieve better patient compliance.
The waterless foams according to the present invention are stable and have better foam quality. Also they are rich in humectants, they provide good moisturisation to the scalp
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and thus cause no drying effect or irritation. Also they Insure better absorption and higher penetration. It is well absorbed with no need of extensive rubbing. The foam is easy to apply and does not leave any residual sticky feeling.
The topical pharmaceutical foam formulation of the present invention further comprises of excipients such as foam adjuvant agents.
The foam composition may further comprise one or more fatty alcohols having 15 or more carbons in their carbon chain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof)- Other examples of fatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well as alcohols with longer carbon chains (up to C50). Fatty alcohols, derived from beeswax, including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain, may especially be well suited as foam adjuvant agents according to the present invention. The concentration of the fatty alcohol, required to support the foam system is inversely related to the length of its carbon chains. Optionally, the carbon atom chain of the fatty alcohol or the fatty acid may have at least one double bond. A further class of foam adjuvant agent according to the present invention may further comprise a long chain fatty alcohol, wherein the carbon atom chain is branched. The carbon chain of the fatty alcohol may be substituted with a hydroxyl group.
The foam adjuvant agent according to one or more embodiments of the present invention may includes a mixture of fatty alcohols and derivatives thereof preferably cetyl alcohol and stearyl alcohol., The fatty alcohol may be used in a range of 0.5% to 10% (w/w) of the carrier mass, preferably the fatty alcohol may be used in a range of 0.5% - 5.0% (w/w) of the carrier mass.
The aliphatic alcohol may preferably comprise one or more of but not limited to ethyl alcohol, isopropyl alcohol, butyl alcohols or mixtures thereof. Ethyl alcohol is found to be more particularly preferred. The aliphatic alcohol may preferably be present in a range of 20% to 60%, most preferably being 20% to 40%(w/w).
Surface-active agents may be suitably selected from but not limited to anionic, cationic, nohionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants. Such surfactants are well known to those skilled in the pharmaceutical and cosmetic formulation art. Nonlimiting examples of possible surfactants include
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polysorbates, such as polybxyethylene sorbitan monostearate (Tween 60) and poly oxyethylene sorbitan monooleate (Tween 80); polyoxyethylene (POE) fatty acid esters, such as Myrj 45, Myrj 49 and Myrj 59; polyoxyethylene alkylyl ethers, such as poly oxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, Brij 38, Brij 52, Brij 56 and Brij Wl ; it may also comprise sucrose esters, partial esters of sorbitol and its anhydrides such as sorbitanmonolaurate , mono or diglycerides, isoceteth-20, sodium methylcocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate triethanolamine lauryl sulfate and betaines. A combination of surface active agents may be used . Any surface-active agent or combinations thereof may be used as surface-active agent. Exemplary non-ionic surfactants include polyethoxylated fatty acids, fatty acid diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, sterol and sterol derivatives, polyethylene ! glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, .polyethylene glycol alkyl phenols, polyoxyethylene- polyoxypropylene block copolymers, sorbitan fatty acid esters and lower alcohol fatty acid esters.
Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Exemplary monoesters may comprise esters of lauric acid, oleic acid, and stearic acid, e. g. , PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20oleate.
Polyethylene glycol fatty acid diesters suitable for use as non- ionic surfactants in the compositions or the present invention may comprise PEG-20 dilaurate, PEG-20 oleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32dio)eate.
Suitable polyethylene glycol glycerol fatty acid esters may further comprise PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PfiG-40 glyceryl laurate, PEG-20 glyceryloleate, and PEG-30 glyceryl oleate.
Among the alcohol-oil transesterified surfactants, preferred hydrophilic surfactants that may be used comprise PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGATO TO), PEG-60 corn glycerides (Crovol
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M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767).
Preferred hydrophobic surfactants in this class that may be used comprise PEG-5, PEG-7, PEG-9 hydrogenated castor oils, PEG-6 corn oil(LabrafilO) M 2125 CS), PEG-6almond oil (Labrafil M 1966 CS), PEG-6 apricot kernel oil(Labrafil (g) M 1944 CS), PEG-6 olive oil(LabrafilO M 1980 CS), PEG-6 peanut oil(Labrafil; M 1969 CS), PEG-6 hydrogenated palm kernel oil (LabrafilO M 2130 BS), PEG-6 palm kernel oil (Labrafil M 2130 CS), PEG-6 triolen (LabrafilO b M 2735 CS), PEG-8 corn oil(LabrafilO WL 2609 BS),PEG-20 corn glycerides(Crovol M40), and PEG-20 almond glycerides (Crovol A40).
The preferred surface active agent is polyethylene glycol - 100 stearate (Myrj - 59). The surfactant may preferably be present in the range of 0.2 to 10%, most preferably being 0.2 to 2.0%.
The present invention further comprises a suitable humectant or mixture thereof. It contains lesser amount of alcohol and is rich in humectants like glycerin, thus causing no drying effect or irritation. The humectants present in the formula also provide a good moisturization to the scalp. The humectant may preferably comprise one or more of but not limited to guanidine, urea, glycolic acid, glycolate salts, ammonium glycolate, quaternary alkyl ammonium glycolate, aloe vera, polyhydroxy alcohol, sorbitol, glycerol, hexanetriol, propylene glycol, butylene glycol, hexylene glycol, a hexylene glycol derivative, polyethylene glycol, a sugar, a starch, a sugar derivative, a starch derivative, alkoxylated glucose, monoethanolamine or mixtures thereof. According to the present invention , preferred suitable mixture of propylene glycol and glycerin gives high humectant effect.The humectant may preferably be present in the range of 10% to 80% , most preferably being 55% to 70% ..
The present invention may further comprise one or more PEG derivatives as a base, in combination with one or more humectants, which are; not limited to PEG-200, 400 along with other derivatives as PEG- 2000, 3350, 4000, 6000, 8000 or any other molecular weight of PEG within the above preferable range.
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The topical pharmaceutical foam may further comprise a hydrocarbon propellant selected from both CFC as well as HFA propellants. The propellants may comprise one or more of n-propane, n-butane, isobutane, dichloromonofluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane, n-pentane, isopentane, dichloro tetrafluoro ethane; 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227)and mixtures of two or more propellants thereof. Preferably the propellant used is Hydrofluorocarbon [HFC 134a]. It is particularly preferred that the propellant may be present in amounts preferably of 3% to 30%w/w, more preferably 7% to 20%w/w, most preferably 5% to 15%w/w.
The formulation of the present invention may be used for treatment of skin disorders such as scalp psoriasis and dermatitis. The topical pharmaceutical foam formulation of the present invention may further comprise various hair styling products for cosmetic use.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be Understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the invention.
Example 1:

Sr. No. Ingredients Qty(% w/w)
1. Betamethasone valerate 0.12
2. Salicylic acid 2.00
3. Cetyl alcohol 2.00
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4. Stearyl alcohol 1.00
5. Glycerin 35.00
6. Polyethylene glycol - 100 stearate 1.00
7. Ethanol 25.00
8. Propylene glycol 33.88
Propellant:
9. .Hydrofluorocarbon (HFC-134a) 10.00
Process :
[1] Cetyl alcohol & stearyl alcohol were dissolved in ethanol.
[2] Polyethylene glycol - 100 stearate was then dissolved in this solution.
[3] Both the drugs viz. betamethasone valerate and salicylic acid were added in the above
mixture & further dissolved.
[4] Finally added propylene glycol and glycerine to it.
[5] The canisters were filled and the propellant was then subsequently charged in it.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants, and the like,
Stability studies:
A study was carried out to evaluate the stability of the Keratolytic agent in aqueous foam
as well as waterless foam.
The results of the stability studies as follows.
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Product : ( Waterless foam composition )
CONDITIO NPARAMET ERS INITIAL 25°C / 60% RH 30°C / 65% RH 40°C/75%RH 2°C-15°C
1 M 3M IM 3M 1 M 3M 1 M 3M
Descriptio n White thick foam Same as initial Same as initial Same as initial Same as initial Same as initial Same as initial Same as initial Same as initial
Assay %
Betamethasonevalerate 101.3 100.9 102.8 97.1 104.5 98.2 97.9 105.0 104.2
Salicylic acid 100.4 100.4 102.3 100.5 . 104.5 100.0 103.1 100.6 103.1

Product : (Aqueous foam composition)
CONDITIO NPARAMET ERS INITIAL 25°C / 60% RH 30°C / 65% RH 40°C/75%RH 2°C-15°C
1 M 3M 1 M 3M 1 IM 3M 1 M 3M
Descriptio n White, thick foam Same as initial Same as initial Same as initial Same as ' initial Same as initial Same as initial Same as initial Same as initial
Assay %
Betamethasonevalerate 102.9 99.8 90.3 100.0 93.8 95.7 92.3 100.2 101.2
Salicylic acid 102.1 82.8 42.9 80.1 34.0 72.1 13.9 100.9 98.9
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Evaluation trial was conducted for both the Aqueous foam & waterless foam
composition under accelerated stability testing at one month & three month interval. The
condition parameters included Assay of the drugs viz. betamethasone valerate & salicylic acid respectively in the foam composition.

The aqueous foam composition evaluation , at one month interval , exhibited consistent results with respect to initial at accelerated temperature & relative humidity conditions viz. 25 deg C/60%RH ; 30 deg C/65%RH ; 40 deg C/75%RH respectively. But, the third month study showed a significant decrease in case of the salicylic acid (keratolytic agent) leading to instability of the aqueous foam composition.
Similar study was carried out with the waterless foam composition under abovementioned conditions. The stability data did not show any significant change in assay even for the three month interval with respect to the initial for both salicylic acid (keratolytic agent) and betamethasone valerate.
Hence, it is confirmed from the above experimental data, that salicylic acid (keratolytic agent) was stable when used with betamethasone valerate in waterless foam composition.
Dated this 3rd day of November 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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