FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"TOPICAL PHARMACEUTICAL 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.

Technical Field:
The present invention relates generally to formulations and methods of providing transdermal or transmucosal delivery of active agents to subjects.
Background and Prior art;
Transdermal and/or transmucosal delivery of active agents provide a convenient, pain-free, and non-invasive method of administering active agents to a subject. Additionally, the administration of active agents, such as drugs, through the skin or mucosal surface avoids the well-documented problems associated with the "first pass effect" encountered by oral administration of active agents. As known in the art, orally administered drugs are absorbed and enter the bloodstream where they are transported by the portal vein directly to the liver before entering the general circulation of the body. If the drug is subject to a high hepatic clearance, i.e., it is rapidly metabolized by the liver, then a substantial fraction of the absorbed dose is extracted from the blood and metabolized before it ever reaches the systemic circulation. The consequence of this "first pass effect" phenomenon is a significant reduction in the bioavailability of the drug. In some instances, the first pass effect is so large as to render oral administration of a drug ineffective.
Although the transdermal and/or transmucosal delivery of active agents overcome some of the problems associated with oral administration of active agents, such as that described above, they are not free of their own drawbacks. Problematically, transdermal drug delivery systems are typically restricted to low-molecular weight drugs and those with structures having the proper lipophilic/hydrophilic balance. High molecular weight drugs, or drugs with too high or low hydrophilic balance, often cannot be incorporated into current transdermal systems in concentrations high enough to overcome their impermeability through the stratum corneum. Specifically, polar drugs tend to penetrate the skin too slowly, and since most drugs are of a polar nature, this limitation is significant.
Efforts have been made in the art to chemically modify the barrier properties of skin to permit the penetration of certain agents (since diffusion is primarily controlled through


the stratum corneum), enhance the effectiveness of the agent being delivered, enhance delivery times, reduce the dosages delivered, reduce the side effects from various delivery methods, reduce patient reactions, and so forth.
In this regard, penetration enhancers have been used to increase the permeability of the dermal surface to drugs, and are often protons accepting solvents such as dimethyl sulfoxide (DMSO) and dimethylacetamide. Other penetration enhancers that have been studied and reported as effective include 2-pyrrolidine, N,N-diethyl-m-toluamide, 1-dodecal-azacycloheptane-2-one N,N-dimethylformamide, N-methyl-2-pyrrolidine, calcium thioglycolate, hexanol, fatty acids and esters, pyrrolidone derivatives, derivatives of 1,3-dioxanes and 1,3-dioxolanes, l-N-dodecyl-2-pyrrolidone-5-carboxylic acid, 2-pentyl-2-oxo-pyrrolidineacetic acid, 2-dodecyl-2-oxo-l -pyrrol idineacetic acid, 1-azacycloheptan-2-one-2-dodecylacetic acid, and aminoalcohol derivatives, including derivatives of 1,3-dioxanes, among others.
The most common penetration enhancers, however, are toxic, irritating, oily, odiferous, or allergenic. Specifically, the penetration enhancers used and thought to be necessary to transdermally deliver active agents such as steroid hormones, namely, compounds such as long chain fatty acids such as oleic acids, fatty alcohols such as lauryl alcohol and long-chain fatty esters such as isopropyl myristate, tend to include aliphatic groups that make the formulations oily and malodorous.
For example, U. S. Pat. No. 5,891,462 teaches the use of lauryl alcohol as a permeation enhancer for estradiol and norethindrone acetate. Such formulations are not appealing to the user nor to anyone else in close proximity to the user. Although this particular patent discloses three examples of estradiol or norethindrone acetate formulations having no lauryl alcohol component, such formulations are comparative examples that are intended to illustrate the long held position that long chain fatty alcohols such as lauryl alcohol are necessary to transdermally deliver norethindrone acetate in combination with estradiol to a subject.
WO0137890 describes a propellant free spray on skin patch composition for improving wound healing and for drug administration. EP 560014, EP6400352 and EP409550 are


among the main prior art documents cited in the search report of the patent application no. WO0137890.
Formulations containing silicone compounds which result in compositions which are pleasant to use are, moreover, known to those skilled in the art.
Thus, in U. S. Pat. No. 6,538,039, a novel formulation of active agent for transdermal administration has been developed, comprising silicone compounds in order to deposit a film at the surface of the skin. In that application also, the transdermal passage is facilitated by the obligatory presence of absorption promoters, namely, among other compounds mentioned, glycols.
French patent application 9405272 discloses a silicone containing topical dosage form comprising a lipophilic active substance, a silicone based adhesive polymer composition and a volatile solvent. This reference, however, requires the use of a large amount of silicone adhesive polymer. These large amounts are not only expensive, but they also make dissolution of the active in the solvent more difficult; they result in a film with inferior aesthetics; they prevent the formulations from being sprayed; and they require a long time for drying.
In EP0966972, the compositions described can be formulated in the form of a spray and comprise an active compound, a silicone gum and a pharmaceutically acceptable excipient. The problem that the invention described in EP0966972 proposes to solve is that of depositing a substantive film at the surface of the skin, which problem is solved by means of the presence of the silicone gum.
In the fields of dermatology and of the formulation of pharmaceutical compositions, those skilled in the art seek compositions which make it possible to release the active agent and to promote its penetration through the layers of the skin in order to improve its effectiveness but does not include agents producing unpleasant odor common to the prior art formulations. The compositions should also be easy to use, non-irritant, having skin tolerability and show a cosmeticity which is acceptable for application to all the regions of the body which may be affected by the pathology.


Object of the invention;
The object of the present invention is to provide a transdermal spray composition so as to bypass the first pass metabolism of pharmaceutical active ingredient.
Another object of the present invention is to provide a transdermal spray composition with convenience, discretion, excellent dispersion, speed and uniformity of application.
Another object of the present invention is to provide a transdermal spray composition without any penetration enhancer/s.
Another object of the present invention is to provide a transdermal spray composition to permit higher active substance flow through skin.
Another object of the present invention is to provide a transdermal spray composition with ease of manufacture.
Another object of the present invention is to provide a transdermal pharmaceutical composition being easy to use, stable and non- irritating, non-odorous and with cosmeticity.
Summary of the Invention:
In a first aspect of the present invention, there is provided a transdermal spray formulation wherein the said transdermal spray formulation comprises (i) a pharmaceutically active agent, (ii) VP/VA copolymer and (iii) a volatile solvent or nonvolatile solvent or a combination thereof.
In another aspect of the invention there is provided a method of administering a pharmaceutically active agent by spraying the said pharmaceutical agent vide transdermal formulation onto the skin of a subject in need thereof.


In another aspect of the present invention, there is provided a method of forming a pharmaceutically active film comprising spraying a transdermal formulation comprising an effective amount of a (i) pharmaceutically active agent, (ii) VP/VA copolymer and (iii) a volatile solvent or non-volatile solvent or a combination thereof on the skin of a subject in need thereof.
In yet another aspect of the present invention, there is provided a process of manufacture of the said formulation thereof.
Detailed description:
The inventors have surprisingly found that the composition comprising, in a pharmaceutically acceptable vehicle: a) a therapeutically effective amount of a pharmaceutical active agent, b) a VA/VP copolymer and c) a volatile solvent or nonvolatile solvent or combination thereof, results in an improvement in penetration of the active agent.
The topical formulation according to the present invention is directed to a substantially malodorous-free and irritation-free transdermal formulation which is substantially free of long chain fatty alcohols, long chain fatty acids, and long-chain fatty esters, and which delivers effective therapeutic levels of an active agent.
The topical formulation of the present invention, while allowing good penetration of the active principles, also showed very good acceptability and tolerance among patients requiring treatment in dermatological conditions, and more particularly very suitable in treatment involving hormone replacement therapy in menopausal women.
The invention relates more particularly to a composition comprising: a) a therapeutically effective amount of a pharmaceutical active agent; b) at least one volatile silicone or atleast one non-volatile solvent or combination thereof; c) a film forming agent, characterized in that the pharmaceutical active agent is an estrogen.
The present invention provides transdermal drug delivery formulations. More specifically, the invention relates to spray formulations for delivering a pharmaceutically


active agent to the skin. In addition to the pharmaceutically active agent, formulations of the invention comprise a VP/VA copolymer and a volatile silicone fluid that preferably volatilizes at mammalian body temperature. Upon application, the present formulations quickly dry to produce a film patch containing the active agent in finely dispersed particles. The film patch is easily washable in water. In some embodiments, patches produced according to the invention provide improved bioavailability of the active agent compared to conventionally utilized methods of topical administration.
As used herein, a "pharmaceutically active agent" refers to an agent that produces a biological effect in in vitro or in vivo systems. The term is intended to include compounds affecting at least one of any therapeutic, prophylactic, pharmacological or physiological response in a subject. More specifically, any active agent that is capable of producing a pharmacological response, either localized or systemic, is within the contemplation of the invention. It should be noted that the active agents might be used singularly or as a mixture of two or more agents or drugs.
As will be understood by those skilled in the art, suitability for transdermal administration of a particular pharmaceutically active agent requires consideration of several factors. For example, prior to incorporating a pharmaceutically active agent in the present formulations, the agent should be evaluated with respect to its permeability through the skin, potential for skin irritation or allergic reaction, pharmacokinetic properties, pharmacodynamic properties, therapeutic window and whether metabolic responses in vivo are consistent with continuous administration.
Non-limiting examples of suitable pharmaceutically active agents that may be used in the present transdermal spray formulations may include, but are not limited to, antiinflammatory drugs, analgesics, antiarthritic drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, antianxiety drugs, narcotic antagonists, antiparkinsonism agents, cholinergic agonists, chemotherapeutic drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistaminics, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs and opioids. Suitable pharmaceutically active agents include


both those that are soluble in aqueous media as well as those soluble in non-aqueous media.
In accordance with the present invention, the hormonal agent is suitably selected from one or more of the group consisting of testosterone, estradiol, ethinylestradiol, progesterone, norethisterone acetate, gestodene, oestriol, oestrone, mestranol, stilbestrol, dienestrol, epiestriol, estropipate, zeranol, allylestrenol, dydrogesterone, lynoestrenol, nestorone, norgestrel, norethyndrel, norethisterone, gestodene, levonorgestrel, medroxyprogesterone, megestrol and MENT (7-methyl-19-testosterone). Particularly preferred among the suitable compounds is estradiol.
The pharmaceutically active agents of the present invention may be present in an amount up to about 40% by weight of the formulation. Estradiol formulations suitably comprise about 0.1% to about 5% of estradiol by weight of the formulation.
The pharmaceutically active agents contained in the present formulation may suitably be included in a variety of forms, depending on the solubility and release characteristics desired. Non-limiting examples of suitable forms include neutral molecules, components of molecular complexes, and pharmaceutically acceptable salts, free acids or bases, or quaternary salts of the same, or as combinations of these. Simple derivatives of drugs such as pharmaceutically acceptable ethers, esters, amides which have desirable retention and release characteristics, and which are easily metabolized at body pH and temperature, may be employed. Enzymes, pro-active forms or pro-drugs are also suitable for use in the present invention.
The formulations of the present invention comprise of VP/VA copolymers. The term "VP/VA" or "vinyl pyrrolidone/vinyl acetate" refers to a copolymer, containing vinylpyrrolidone (also referred to as N-vinylpyrrolidone, N-vinyl2-pyrrolidone and N-vinyl-2-pyrrolidinone) as a monomeric unit. The copolymer vinylpyrrolidone-vinyl acetate is generally known in the pharmaceutical industry under the designations Copolyvidone, Copolyvidonuin or VP-VA (or VP/VA as used herein). VP/VA series products play a good role in film-former. Its hygroscopicity decreases with the increase of


the proportion of vinylacetate in the molecule. This property of VP/VA is extremely useful as it works in sprays and lotions. Also, VP/VA copolymers are primary film formers for a variety of products which demand different degrees of water resistance including aerosol, aqueous, and organic solvent systems. These polymers exhibit film flexibility, good adhesion, luster, water remoisten ability, and hardness.
The VP/VA copolymer may be present in an amount between about 0.1% to about 20% by weight of the formulation. In another embodiment, the VP/VA copolymer may be present in an amount between about 0.1% by weight to about 5% by weight of the formulation. In another embodiment, the VP/VA copolymer may be present in an amount between about 0.1% by weight to about 3% by weight of the formulation.
The VP/VA copolymer may comprise any proportion of vinylpyrrolidone to vinyl acetate. Preferably the VP/VA copolymer may comprise from 50 to 70 weight % vinylpyrrolidone. In one embodiment, the VP/VA copolymer comprises 60 weight % vinylpyrrolidone.
According to the invention, the term "volatile silicone" is intended to mean polyorgano-siloxane compounds, which may be cyclic or linear, having a measurable pressure under ambient conditions.
The cyclic volatile silicones according to the invention are polydimethylcyclosiloxanes, i. e. compounds of formula [-Si (CH3)2-0-] n with n being, on average, between 3 and 6, and preferably n=4 or n=5, generally known as cyclomethicones. The linear volatile silicones according to the invention are linear polysiloxanes such as hexamethyldisiloxane or low molecular weight dimethicones. The linear volatile silicones generally have a viscosity of less than approximately 5 centistokes at 25°Celsius, whereas the cyclic volatile silicones have a viscosity of less than approximately 10 centistokes at 25°Celsius.
Preferred volatile silicones according to the invention are the linear siloxanes, and more preferably hexamethyldisiloxane. By way of example, mention may be made of the product sold by the company DOW CORNING, DC Fluid 0.65cSt.


Dow Corning provides a commercial product sold under the name DC Silmogen Carrier, which is made up of 99% of hexamethyldisiloxane and 1% of silicone gum, which product may advantageously be used in one of the compositions according to the invention.
The pharmaceutically acceptable vehicle according to the invention should be chosen such that the advantageous properties intrinsically associated with the present invention are not, or are not substantially, altered by the envisaged addition.
Preferably, the vehicle used according to the invention is chosen so as to be an agent which solubilizes the active agent. The active agent-solubilizing vehicle may be made up of a single excipient, such as a solvent, or of a mixture of excipients, such as those used for the formulation of an emulsion. By way of nonlimiting examples of excipients which may be used alone or as a mixture, mention may be made of water, solvents, diluents, and any excipient which can be used for the formulation of an emulsion, of milk, of a gel, of an ointment, or of a foaming composition. These excipients are compounds commonly used in the formulation of a pharmaceutical composition. Preferably, the active agent-solubilizing excipients according to the invention are water, alcohols, polyols, ethers, esters, aldehydes, ketones, fatty acids and fatty alcohols, and fatty esters. More preferably, the excipient used will be an alcohol. According to the invention, the term "alcohol" is intended to mean linear or branched aliphatic alcohols such as ethanol, propanol or isopropanol.
In a preferred embodiment according to the invention, the vehicle used will therefore be alcoholic.
According to the invention, the term "alcoholic vehicle" is intended to mean a vehicle comprising at least 15% of alcohol, and preferably at least 25% of ethanol.
The pharmaceutical composition according to the invention may also contain inert additives or combinations of these additives, such as: wetting agents; flavour enhancers; preserving agents; stabilizers ; moisture regulators; pH regulators; osmotic pressure modifiers; emulsifiers; UV-A and UV-B screening agents; propenetrating agents;


antioxidants ; and synthetic polymers.
Of course, those skilled in the art will take care to choose the possible compound (s) to be added to these compositions in such a way that the advantageous properties intrinsically associated with the present invention are not, or are not substantially, altered by the envisaged addition.
The composition according to the invention is more particularly intended for treating the skin and the mucous membranes, and may be provided in the form of ointments, creams, milks, salves, powders, impregnated pads, syndets, solutions, gels, sprays, foams, suspensions, lotions, sticks, shampoos, pledgets or washing bases. It may also be provided in the form of suspensions of lipid or polymer vesicles or nanospheres or microspheres or polymer patches and hydrogels to allow controlled release. This topical-application composition may be provided in anhydrous form, in aqueous form or in the form of an emulsion.
The composition according to the invention showing improved penetration is preferably administered in the form of a sprayable composition. In order to be sprayable, the compositions according to the invention will preferably have a viscosity of less than 50 centistokes.
The sprayable form, or spray, can be obtained by conventional formulation means known to those skilled in the art. For example, the composition may be sprayed by means of a mechanical spraying device which pumps the composition from a container, bottle or equivalent. The composition passes through a nozzle which can be aimed directly at the desired site of application. The nozzle can be chosen so as to apply the composition in the form of vaporization or of a jet of droplets, according to techniques known to those skilled in the art. According to the pharmaceutical active agent chosen, the spraying mechanism must be capable of always delivering the same amount of active agent. The mechanisms for controlling the amount of composition to be delivered by the spray are also known to those skilled in the art.


Alternatively, the topical formulation according to the present invention may further comprise use of propellants (e.g. CFC or HFA) which may be administered in a suitable metered dose spray device.
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 present invention.

Sr. No. Ingredients Qty / Unit (% w/w)
1 Estradiol 0.27
2 Copovidone Ph. Eur (Kollidon VA64) 2.50
3 Q7-9180 Silicone fluid (0.65 est) 20.00
4 Ethanol q. s. to 100%
According to the preferred embodiment, the pharmaceutical composition may be processed by conventional methods as known to a person skilled in the art:
(1) Kollidon VA64 was dissolved in ethanol.
(2) To the above solution, Q7-9180 silicone fluid was added and mixed.
(3) Finally, estradiol was dissolved in the solution obtained in step (2) to get a clear solution.
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 diluent" includes a single diluent as well as two or more different diluents, reference to a "disintegrant" refers to a single disintegrant or combination of two or more disintegrants, and the like.