FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"TOPICAL COMPOSITION"

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 describes the invention.

Field of Invention
The present invention relates to a topical composition for the treatment and protection of animals which are infested with parasites or likely to be infested with them. In particularly, the aim of the invention is to provide an antiparasitic composition for treatment and protection of animals.
Background and prior art
Pets are often infested with one or more of the parasites such as cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp. and the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyoma sp. and the like), galls (Demodex sp., Sarcoptes sp., Otodectes sp. and the like).
Fleas cause an animal a great deal of stress and are harmful to its health. Moreover, fleas are also vectors of pathogenic agents, such as dog tapeworm (Dipylidium caninum), and can also attack man. Similarly, ticks can also cause an animal stress and be harmful to its health. They can also be harmful to man. However, the most serious problem of ticks is that they are the vector of pathogenic agents which may affect the animal as much as man.
Among the major diseases which need to be avoided, mention may be made of borrelioses (Lyme disease caused by Borrelia burgdorferi), babesioses (or piroplasmoses caused by Babesia sp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks can also release toxins with paralysing and inflammatory properties, these toxins occasionally being fatal. Lastly, galls are particularly difficult to combat since there are very few active substances which act on these parasites, and they require frequent treatment.
At present, there are number of more or less active insecticides are available. However, phenomena of resistance are often associated with their use, as is the case, for example, with carbamates, organophosphorus compounds and pyrethroids.

A new family of insecticides based on 1-N-phenylpyrazoles has been described in WO87/03781, EP295117 and EP352944. The compounds of the families defined in these patents are extremely active and one of these compounds, l-[2, 6-Cl2-4-CF3phenyl]-3-CN-4-[SO-CF3]-5-NH2 pyrazole, the common name of which is Fipronil, has proved to be having a very broad spectrum activity including parasitic activity and particularly effective, not only against crop parasites but also against ectoparasites of mammals and in particular, but not exclusively, fleas and ticks.
Commercially available formulations of Fipronil are FRONTLINE(R) from Merial, Inc, TREMIDOR{R), TOP SPOT(R) and ADONIS(R) from Aventis CropScience S.A., Lyon, France.
US6395765 (to Merial Lyons, filed on September 25, 1996) discloses a topical composition in the form of a ready-to-use solution comprising Fipronil.
US6482425 (to Merial Lyons, filed on March 17, 1999) discloses a spot-on composition containing Fipronil and an endectocidal parasiticide of the macrocyclic class of compounds selected from the group consisting of avermectin, abamectin and doramectin;
US6797724 (to Merial Lyons, filed on April 11, 2002) discloses a direct pour-on skin solution, comprising compounds that degrade; e.g. biodegrade, photodegrade or chemically degrade, to phenylpyrazoles and other excipients.
EP0296381 (to Bayer AG, filed on December 28, 1988) describes pyrazole compounds having insecticidal activity in the field of agriculture, public health and veterinary medicine. Boophilus microplus is one of the many targets mentioned.
Other methods for administering pyrazole compounds include placing the therapeutic agent in a solid or liquid matrix for oral delivery. These methods include chewable drug-delivery formulations (WO2004016252 to Merial Limited, filed on August 14, 2003). The problem associated with oral formulations is that the therapeutic agent often provides an unpleasant taste, aroma, or mouth-feel to the formulation, which cause, especially in the situation with animals, the oral formulation to be rejected by the animal.

Patent Application AU16427/95 mentions the combination of a substituted 1-N-pyrazole derivative of this type with avermectins, ivermectin or moxidectin, among a very large number of insecticides or parasiticides of various types, including Fipronil, however, without giving information on a composition comprising such a combination and without establishing a distinction regarding the susceptible targets by specific combinations, among the innumerable parasites which can potentially be attacked.
Most of the prior art ant i-parasitic formulations employs crystallization inhibitors (such as low molecular weight polyvinylpyrrolidone, copolymers of vinyl acetate and vinyl pyrrolidone and polyoxyethylenated sorbitan esters).
Although it is known that surfactants may also be used in combination with crystallization inhibitors but selection of a specific surfactant in combination with a specific crystallization inhibitor is challenging because of incongruity between various surfactants and crystallization inhibitors in serving its intended purpose.
Improper selection of surfactant may reduce the inhibiting effect of crystallization inhibitor and hamper its intended purpose in the product. For example, both non-ionic PEG-10-olylether and hexadecylpyridinium cations reduce the inhibiting effect of PVP on crystallization. (K. H. Ziller et al., Control of crystal growth in drug suspensions, 1988, Drug Development and Industrial Pharmacy, 14 (15-17), 2341 -2370).
Also, in the presence of some polymers, surfactant molecules may associate with polymers to form surfactant-polymer aggregates (complexes). (Fang Li. Et. al., 1998, Colloid PolymSci 276:1-10).
Some surfactants however, may hinder protective action of crystallization inhibitors on drug almost completely. For example, the surfactant 'hexadecyl sulphate' aggregates with PVP in aqueous phase and thus prevents PVP from establishing protective layers on the drug particles.

In one particular example using acetaminophen (Saito, S., T. Taniguchi and K. Kitamura. J. Coll. Int. Sci. 37 (1971), 154-164), surfactants may disturb the structure of protective layer of crystallization inhibitors at the drug surfaces leading to further crystallization of acetaminophen.
The said combination should also be miscible and suitable with the solvent system of the anti-parasitic composition.
Hence, there still exists a continuing need to select a proper combination of crystallization inhibitor and surfactant in the antiparasitic formulations so as to overcome the shortcomings of prior art.
Objects of the invention
The object of the invention is to provide a topical composition which, when applied locally, will subsequently spread over the animal's entire body and then dry, while at the same time avoiding any phenomenon of crystallization over a significant time period.
Another object of the invention is to provide topical antiparasitic compositions for the treatment and protection of animals, these compositions being of great efficacy while at the same time being easy to use.
Yet another object of the invention is to provide a topical composition which is easy to use on any type of domestic animal, irrespective of its size and the nature of its coat.
Yet another object of the invention is to provide a topical composition which is effective and which is not required to be sprinkled over the animal's entire body.
Yet another object of the invention is to provide a topical composition which, after drying, gives good appearance and feel of non-sticky coat after application.
Still another object of the present invention is to provide a topical composition with ease of manufacture.

Summary of the invention
According to one aspect of the present invention, there is provided a topical composition comprising Fipronil or its pharmaceuticaHy acceptable salts, pharmaceuticaHy acceptable solvates, pharmaceuticaHy acceptable enantiomers, pharmaceuticaHy acceptable derivatives, pharmaceuticaHy acceptable polymorphs or pharmaceuticaHy acceptable prodrugs; atleast one crystallization inhibitor and atleast one surfactant with one or more pharmaceuticaHy acceptable excipients.
According to another aspect of the present invention there is provided a topical composition comprising combination of Fipronil with one or more anti-parasitic agent/s or its pharmaceuticaHy acceptable salts, pharmaceuticaHy acceptable solvates, pharmaceuticaHy acceptable enantiomers, pharmaceuticaHy acceptable derivatives, pharmaceuticaHy acceptable polymorphs or pharmaceuticaHy acceptable prodrugs; atleast one crystallization inhibitor and atleast one surfactant with one or more pharmaceuticaHy acceptable excipients.
According to yet another aspect of the present invention, there is provided a process of manufacture of a topical composition comprising Fipronil or its pharmaceuticaHy acceptable salts, pharmaceuticaHy acceptable solvates, pharmaceuticaHy acceptable enantiomers, pharmaceuticaHy acceptable derivatives, pharmaceuticaHy acceptable polymorphs or pharmaceuticaHy acceptable prodrugs; atleast one crystallization inhibitor and atleast one surfactant, with one or more pharmaceuticaHy acceptable excipients.
Detailed Description
As described hereinbefore, there is a continuing need of an antiparasitic composition which is efficacious, easy to use, and avoids crystallization of active over a significant time period.

It has been surprisingly found that a suitable combination of surfactant such as polyoxyethyienated castor oil derivatives and crystallization inhibitors resulted in inhibition of crystallization of active over a significant time period.
In particular, it has been found that the surfactant, polyoxyethyienated castor oil derivatives are most suitable and serve all the purpose of the present invention.
Polyoxyethylene castor oil derivatives are complex mixtures of various hydrophobic and hydrophilic components. These compounds are non-ionic surfactants which are approved for use in oral, topical, and parenteral pharmaceutical formulations. The polyoxyethylene castor oil derivatives are mainly used as emulsifying and solubilizing agents for the production of aqueous liquid preparations containing oils or hydrophobic drugs. Examples of these compounds which are suitable for use in the present invention may be selected from, but not limited to polyoxyethylene 5 castor oil (Acconon CA-5), polyoxyethylene 9 castor oil (Acconon CA-9), polyoxyethylene 15 castor oil (Acconon CA-15), polyoxyethylene 35 castor oil (Cremophor EL, Cremophor ELP, Etocas 35), polyoxyethylene 40 castor oil, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40, Emulgin HRE 40), polyoxyl 40 hydrogenated castor oil (Emulgin HRE 60).
The amount of the polyoxyethylene castor oil derivatives in the topical composition ranges from 1% to 20 % w/w of the composition, preferably present at a concentration of 1 to 15% w/w by weight of the composition.
It will be well appreciated to the person skilled in the art that the anti-parasitic composition according to the present invention may be achieved by using a surfactant selected from, but not limited to, non-ionic surfactants such as polyoxyethyienated esters of sorbitan (e.g. polysorbate 20, polysorbate 60 & polysorbate 80); propylene glycols and fatty acid esters of propylene glycol (e.g. propylene glycol monocaprylate, propylene glycol monolaurate); oleoyl macrogoi glycerides (e.g. Labrafil); Caprylocaproyl macrogol glycerides (e.g. Labrasol); polyethylene glycols (e.g. PEG 600, PEG 6000); copolymers of ethylene oxide & propylene oxide (e.g. Poloxamers) or combinations thereof.

A crystallization inhibitor is an agent which prevents crystallization of the drug from the composition in the container or the hair or skin of the animal.
The crystallization inhibitor used in the present invention, may be selected from, but not limited to polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose; acrylic derivatives such as methacrylates and the like, anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of formula N+R'R"R'"R"" Y" in which the radicals R are hydrocarbon radicals, optionally hydroxylated, and Y is an anion of a strong acid such as halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used, amine salts of formula N+R'R"R'" in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, nonionic surfactants such as optionally polyoxyethylenated sorbitan esters, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, lauryl-substituted betaine compounds, or a mixture of at least two of these crystallization inhibitors.
The amount of crystallization inhibitor in the topical composition ranges from 1 to 20% w/w by weight of the composition, and more preferably 1 to 15% w/w by weight of the composition.
According to a preferred embodiment, the topical composition comprises Fipronil or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs; atleast one

crystallization inhibitor and atleast one surfactant with one or more pharmaceutical ly acceptable excipients.
According to another preferred embodiment, the topical composition further comprises one or more additional anti-parasitic agents selected from, but not limited to insect growth regulators such as methoprenes, pyriproxyfens, hydroprene, cyromazine, lufenuron and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea; compounds which mimics juvenile hormones such as azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2-(2-chloro-2-methyl-propyl)-5-(6~iodo-3-pyridylmethoxy)-pyridizi ne-3(2H)-one; chitin-synthesis inhibitors such as chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flueycloxuron, flufenoxuron, hexaflumuron, lufenuron, tebufenozide, teflubenzuron, triflumuron, l-(2,6-difluorobenzoyl)-3-(2-tluoro-4- (trtfluoromethyl)phenylurea,l-(2,6-difIuoro-benzoyl)-3-(2-fIuoro-4-(l.l,2, 2-tetrafluoroethoxy)-phenylurea and l-(2,6-difluoro-benzoyI)-3-(2-fluoro-4-trifiuoro-methyl)phenylurea or their pharmaceutical^ acceptable salts, pharmaceutical^ acceptable solvates, pharmaceutical ly acceptable enantiomers, pharmaceutical^ acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutical acceptable prodrugs thereof. An exemplary combination is fipronil and S-methoprene.
The organic solvent used in the topical composition according to the present invention preferably has a dielectric constant of from 10 to 35, preferably from 20 and 30. The content of this organic solvent in the total composition preferably represents the remainder to 100% of the composition. The organic cosolvent preferably has a boiling point lower than 100°C; preferably lower than 80°C, and a dielectric constant of from 10 to 40, preferably of from 20 to 30. The cosolvent is preferably present in the composition according to a w/w ratio of co-solvent/solvent of from 1/15 to 1/2. The cosolvent is volatile in order to promote drying and is miscible with water and/or with the solvent.
An organic solvent used in the topical composition according to the present invention, may be selected from, but not limited to acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol

monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone. diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of these solvents. The preferred solvent is selected from glycol ethers, in particular diethylene glycol monoethyl ether.
Examples of cosolvents for use in the topical composition according to the present invention comprise alcohols, such as ethanol, isopropanol, and methanol and present in the proportion of 0 % wAv to 20 % w/w of the composition.
As antioxidant, standard agents may be used in particular, such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate, a mixture of of these antioxidants.
The amount of antioxidant in the topical composition according to the present invention ranges from 0.005 to 1% w/w of the composition, preferably 0.005 to 0.05% w/w of the composition.
Although water is not preferred, the topical composition according to the present invention may optionally contain water in a proportion of from 0 to 30% w/w of the composition, preferably, from 0 to 5% w/w of the composition.
Oils may advantageously be utilized in the topical compositions of the invention. For example, heavy oils such as mineral or vegetable including corn, soybean and peanut oil, and petroleum fractions such as paraffinic or aromatic hydrocarbons may be used.
The composition so made up achieves, in a noteworthy manner, the absence of crystallization on the hair or skin and of maintenance of the cosmetic appearance of the coat that is to say a tendency not to stick together or to have a sticky appearance, despite high concentration of active substance.
The topical composition according to the invention intended for animals may be applied by deposition on the skin ("spot on" or "pour on" application); this may be a localized

application in particular at two points and preferably localized between the animal's shoulders. After deposition, the composition diffuses, in particular over the animal's entire body, and then dries, without crystallizing or changing the appearance (in particular absence of any whitish deposit or of any dusty appearance) or the feel of the coat.
The topical composition according to the invention is particularly advantageous on the grounds of its efficacy, its speed of action and the pleasant appearance of the animal's hair after application and drying.
The present invention also provides a process to manufacture the antiparasitic topical
composition, which process comprises-
(a) Adding surfactant & crystallization inhibitor in a part quantity of organic solvent.
(2) Warming the bulk of step (1) to dissolve the surfactant and crystallization inhibitor followed by addition of antioxidants and the mixture is allowed to cool.
(3) Adding the active ingredient to the above mixture under stirring followed by addition of cosolvent and finally making up the weight with remainder of organic solvent and mixing.
In a preferred embodiment according to the present invention, there is also provided use of the topical composition for treating and/or protecting (preventive care) of animals against parasites, according to which an effective volume of a composition according to the invention is applied to a limited area of the animal, as is described above. The application is advantageously made at two points and/or on the animal's back between the shoulders.
The purpose of application of the topical composition of the present invention may be non-therapeutic, when it concerns cleaning the animal's hair and skin by eliminating the parasites present as well as their residues and excreta. The animal thus has a coat which is pleasant to look at and to feel. This also makes it possible to prevent the establishment of fleas in the house.
The purpose of application of the topical composition of the present invention may also be therapeutic when it concerns treating a parasitosis which has pathogenic consequences.

The volume applied may be about 0.3 to 1 ml, preferably about 0.5 ml for cats, and about 0.3 to 3 ml for dogs, or to any animal depending on its weight.
The volume of composition applied preferably corresponds to a dose of Fipronil of between 0.3 and 60 mg, in particular of between 5 and 15 mg, per kg of body weight of the animal.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1
Topical formulation of Fipronil

Sr. No. Ingredients Qry in %w/w

Formula 1 Formula 2
I Fipronil 9.7 9.7
2 Ethanol 5 7.5
3 Butylated Hydroxy Anisole 0.02 0.02
4 Butylated Hydroxy Toluene 0.01 0.01
5 Polyethylene glycol 60 Hydrogenated castor oil 5 5
6 Polyethylene Glycol 1000 5 7.5
7 Diethyl glycol monoethyl ether q. s. to 100 gm q. s. to 100 gm
Process:
(1) Polyethylene glycol 60 hydrogenated castor oil & polyethylene glycol 1000 were
added in 50% w/w batch quantity of diethyl glycol monoethyl ether.
(2) The bulk of step (1) was warmed to dissolve both polyethylene glycol 60
hydrogenated castor oil & polyethylene glycol 1000 followed by addition of butylated
hydroxy toluene and butylated hydroxy anisole and the mixture was allowed to cool.

(3) Fipronil was added to the above mixture under stirring followed by addition of ethanol and finally the weight of the formulation was made with diethyl glycol monoethyl ether and mixed.
Example 2
Topical formulation of Fipronil and s-methoprene

Sr.
No. Ingredients Formulation for CAT Formulation for DOG

Formula 1
Qty in % w/w Formula 2
Qty in % w/w Formula 1
Qty in % w/w Formula 2
Qty in % w/w
1 Fipronil 9.80 9.80 9.80 9.80
2 S- Methoprene 11.80 11.80 8.80 8.80
3 Ethanol 5.00 7.50 5.00 7.50
4 Butylated Hydroxy Anisole 0.02 0.02 0.02 0.02
5 Butylated Hydroxy Toulene 0.01 0.01 0.01 0.01
6 Polyethylene glycol 60 Hydrogenated castor oil 5.00 5.00 5.00 5.00
7 Polyethylene Glycol 1000 5.00 7.50 5.00 7.50
8 Diethylene glycol monoethyl ether q. s. to IOOgm q. s. to IOOgm q. s. to IOOgm qsto IOOgm
Process:
(1) Polyethylene glycol 60 hydrogenated castor oil & polyethylene glycol 1000 was added in 50% w/w batch quantity of diethyl glycol monoethyl ether.
(2) The bulk of step (1) was warmed to dissolve both the polyethylene glycol 60 hydrogenated castor oil & polyethylene glycol 1000 followed by addition of butylated hydroxy toluene and butylated hydroxy anisole and the mixture was allowed to cool.
(3) Fipronil was added to the above mixture under stirring followed by addition of s-methoprene & ethanol and finally the weight of the formulation was made with diethyl glycol monoethyl ether and mixed.

Stability studies were conducted on the antiparasitic compositions of the present invention and innovator product. Results of which are tabulated below-
Stability study data for Fipronil Spot-on formulation (9.7 % w/w of Fipronil, 5% w/w of ethanol, 5% w/w of polyoxyethylene castor oil & 5% w/w PEG 1000)

Condition Assay Impurity

% Single max % Total
Initial 102.9 1.037 1.3
lM25°C/60%Rh 97.43 1.016 1.363
lM30°C/70%Rh 99.64 1.046 1.401
!M40°C/75%Rh 104.25 1.09 1.501
Stability study data for Fipronil Spot-on formulation (Innovator product)

Condition Assay Impurity

% Single max % Total
Initial 102.62 1.99 4.774
lM30°C/35%Rh 98.97 1.993 4.283
!M40°C/20%Rh 102.53 2.037 4.523
The stability study results show that the anti-parasitic formulation of the present invention is relatively stable in comparison to the innovator product over one month storage period.
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 spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those

skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
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 and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus: for example, reference to "a preservative" includes a single preservative as well as two or more different preservatives; reference to a "surfactant" refers to a single surfactant or combination of two or more surfactants, and the like.