DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

ORAL FILMS OF ANTI-EMETIC DRUGS

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500078, Telangana, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to new oral dosage forms of Anti-emetic drugs and its pharmaceutically acceptable salts thereof, for veterinary use, such as for oral administration to animals. More specifically the present invention relates to oral film compositions comprising Anti-emetic drugs and its pharmaceutically acceptable salts thereof and method of administering the same to the oral cavity of the animals in treating or preventing Nausea and Vomiting.

BACKGROUND OF THE INVENTION
Due to a rapid growth in per capita income globally and improvement of people's living standards, the culture of maintaining domestic animals or pets as house hold has raised. The pet population has grown drastically over the period of year. Dogs are the most popular pets in households, while cats have become the second-preferred option, followed by fish and birds. Other pets, such as dogs used for police work and search and rescue operations, race horses etc each play a significant role in society. On another side, Animal husbandry and Dairying is a critical industry for ecological and environmental survival. Animal husbandry requires continuous nurturing of animals for meat, fibre, milk or for aiding agricultural purposes. As the Animal husbandry, Dairying and pet culture diversified over years, effective veterinary care is also growing on par with culture. Currently, veterinary care has become very important to the animal owners as well as the rest of society. The proper and efficient veterinary care of these pets and other animals is very important for overall ecosystem development.

Accordingly, demand for high quality and ease of administering the animal medicines has also seen a growth, as these animals are been periodically medicated with antibiotics, anti-inflammatory agents, anti-viral agents, vaccines and wormers, which are important to the health of these animals or pets and occasionally with medicines for treating metabolic disorders, such as cancers. All these periodical and occasional medications could induce irritations and initiate emesis. Another major cause of nausea or vomiting in the animal is motion sickness, where the pets are been carried by the owner while travelling in a car, boat or airplane.

To treat or prevent such inducement or triggering of emesis (nausea or vomiting) in pets, there are several anti-emetic drugs are been administered along with primary periodical or occasional medications or administered before taking the pets or animals for a journey in Car, Boat or aeroplane travel.

Emesis (Vomiting or Nausea) is caused when impulses from the chemoreceptor trigger zone (CRTZ) in the brain are sent to the vomiting centre in the medulla. Motion sickness specifically occurs when signals to the CRTZ originate from the inner ear motion is sensed by the fluid of the semi-circular canals, which causes overstimulation. These signals travel to the brain’s vestibular nuclei, then to the CRTZ, and finally to the vomiting Center. NK-1 receptor antagonists act by inhibiting the binding of substance P, a neuropeptide of the tachykinin family. Substance P is found in significant concentrations in the nuclei comprising the emetic centre and is considered the key neurotransmitter involved in vomiting.

There are several regulatory approved anti-emetic drugs available in the market. Among them Neurokinin-1 (NK-1) receptor antagonists or inhibitors, that possesses unique anxiolytic, antidepressant, and antiemetic properties. By inhibiting the binding of substance P within the emetic centre, these NK-1 receptor antagonists are effective against neural and humoral (central and peripheral) causes of vomiting or Nausea. Maropitant is the only approved anti-emetic in the class neurokinin-1 receptor inhibitor for treating or preventing vomiting or nausea for animals, specifically pets like Dogs and cats.

According to the book “Small Animal Clinical Pharmacology” edited by JE Maddison et al., published in 2008 by Elsevier, Maropitant, when compared to other anti-emetics has similar or greater effectiveness to chlorpromazine (a dopaminergic antagonist) and metoclopramide (a serotonergic antagonist) for centrally-mediated vomiting (caused by direct stimulation to the vomiting Center in brain) induced by apomorphine or xylazine (dopamine agonist).

Cited from the book “Textbook of Veterinary Internal Medicine” Vol-1 by Stephen J. Ettinger, et al., published in 2010 by Elsevier. Maropitant works better than chlorpromazine and metoclopramide for peripheral-induced vomiting (caused by actions in the gastrointestinal tract) induced by syrup comprising emetic.

In the article titled “Maropitant: Novel Antiemetic” by Lauren A. Trepanier published in 2015, it is known that unlike dimenhydrinate (histaminergic antagonist) and acepromazine (dopamine antagonist), which are used for motion sickness, maropitant does not cause sedation.

Maropitant, as maropitant citrate (C32H40N2O.C6H8O7·H2O ) was known to be approved in European countries as tablet (16mg, 24mg, 60mg, or 160mg) dosage form in September 2006 to Zoetis (a Pfizer subsidiary) for use in Dogs under the brand name CERENIA®. Later, an Injectable Solution comprising 10mg/ml of maropitant citrate for use in Dogs and Cats was approved. CERENIA® is approved for the treatment of nausea and vomiting in dogs and cats.

Some non-limiting examples of other USFDA approved Anti-emetic drugs for use in animals are Aminopentamide hydrogen sulfate, a cholinergic blocking agent or antispasmodic, was known to be approved in USA under the brand name of Centrine® 0.2mg Tablets. Acepromazine maleate, a dopamine receptor antagonist at CRTZ in brain, was approved in USA under the brand name PromAce® 5, 10, or 25 mg tablets and 50mg/ml injection. Promazine Hydrochloride and Triflupromazine Hydrochloride was also known as dopamine receptor antagonist, approved in USA under the brand name Sparine® 100mg tablets, injections and Vetame® 10mg and 25mg tablets respectively.

WO1992021677 publication discloses Maropitant and methane sulfonate salt of maropitant and use of the same in mammals as substance P antagonist (Substance P is a peptide composed of a chain of 11 amino acid residues; member of the tachykinin neuropeptide family) and the specification also generically discloses several possible dosage forms like, tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like, in which maropitant can be incorporated. Further, it lists several ailments and conditions that can be prevented, of which are majorly rely on decrease in substance P mediated neurotransmission.

European patent EP0627221 discloses multiple compounds of NK-1 receptor antagonist which explicitly covers Maropitant for use in Emesis in mammals, which includes the treatment of Nausea and Vomiting. The specification also lists suitable pharmaceutically acceptable salts of NK-1 antagonists, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. This patent also discloses wide variety of different dosage forms, i.e., tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like, which may be formed by combination of various pharmaceutically acceptable inert carriers, like wise generically listed excipients suitable for oral and parenteral administration.

WO2000073304 publication discloses citrate salt of Maropitant, stable and drug regulatory approved monohydrate crystalline polymorphic Form A of Maropitant citrate and process of preparing the same. The specification also discloses effective dosages of crystalline maropitant citrate for oral administration in mammals i.e., 2.5mg/day to 160mg/day and preferable 5-80mg/day of monohydrate form in a single or divided dosage administered via pills or tablets or injections.

U.S. patent No. 8,183,230 discloses effective Maropitant comprising specific parenteral pharmaceutical composition for systemic administration in animals.

European patent No. 3,173,071 and U.S. patent No. 9,974,742 discloses injectable compositions comprising maropitant citrate.

CN109172547A patent publication discloses self-micro emulsifying oral quick-dissolving films for pets, which comprises self-microemulsifying component, film-forming material, plasticizer, disintegrant, thickener, and flavouring agent. Self-micro emulsifying components are composed of an oil phase, an emulsifier and a co-emulsifier; the oil phase can be castor oil, olive oil, oleic acid, ethyl oleate, medium chain triglycerides, a mixture of one, two or more of glyceryl oleate and isopropyl myristate; the emulsifier can be selected from polyethylene glycol glycerides, polysorbates, and polyoxyethylene castor oils. The co-emulsifier can be one, two or more mixtures of ethanol, propylene glycol, glycerin, polyethylene glycol, and diethylene glycol monoethyl ether.

WO2016073347 patent publication discloses and refers a stable, palatable, soft chewable oral composition for increased acceptance of the medication in animals, which show resist swallowing hard tablets or capsules and chewing bitter and/or granular dosage forms. Soft chew is referred to a ductile composition, where it is a supple, pliable, flexible form, i.e., is not a brittle form. Specification discloses suitable non-limiting excipients of binding agent, disintegrant, wetting agent, flavorant (meat or vegetables), filler, antioxidant, colorant and taste masking agent. The flavorant is used as an admixture with filler. Soft chewables are prepared by extrusion technique, where above excipients were extruded to a desired shape on a die and cut into individual units for administration. It also exemplified a soft palatable chewable composition comprising Maropitant, Microcrystalline cellulose (binding agent), disintegrant, glycerol (wetting agent), flavorant/filler and Polyvinylpyrrolidone (taste masking agent). Though a simple method of administering but it is limited by several additional factors such as complete and sufficient chewing of the dosage form, capacity of animal or pet to chew, reluctance and compliance of the animal or pet to chew, splitting out the half chew or dogs drooling etc., which effects the release of drug and effective treatment.

U.S. patent publication No. 20050136096 discloses edible films for administration of medicaments to animals, wherein the edible film disclosed has an applied coating and a thin film. The applied coating is a powder matrix including one or more medicaments optionally with a carrier is applied as a coating by Sifting, Screening, atomization, Static, mechanical agitation or fluidization etc. Though the disclosure does not disclose any anti-emetic drugs or films comprising the same, such edible films are limited by animal’s oral mucosa is being directly exposed to the drugs applied over the film, that may be cause sense of irritability or drooling when administered, resulting in dosing error and reluctance to take such films from next dose onwards. Also, the coated medicament on the thin film may be eroded during the process of administration i.e., while taking out from the package and handling it while administering to the animal.

It is well known from the arts that the methods of administering Anti-emetic drugs and its pharmaceutically acceptable salts thereof to animals include vascular injections, muscular injections and oral administration of liquids or tablets or pills or soft chewables or drug coatings on oral thin films. Disadvantages of these known pharmaceutical delivery methods include difficulty swallowing, difficulty in administration, inconvenience to pet medical staff and pet owners, pain to the animals, cause damage to oral cavity or oesophagus with auxiliary feeders, erosion of drug coating on thin films and difficulty in measuring the dosages when liquids or tablets or pills are added to animal feed, since, for example, some time a number of animals or pets will share a common feed container and animals will sometimes try to spit out the medicament, which reduces therapeutic effect in the target animals.

Parenteral dosage forms are difficult in administration, also cause pain to the animals, maximum attention while administering and pose a danger of self-administering or injury to the administrating volunteer like pet nursing staff during the process of injecting. Moreover, the administration is a like an operative procedure, which requires medical attendant and accompanying staff. Thus, there is need for an effective, pliable, easily administrable dosage form for the pet owner or any volunteer with required minimal attention.

Solving the problems of pets or animal’s reluctance to swallow and poor compliance to known dosage forms has become the focus of the development of new or alternate dosage forms for oral administration of animals. Accordingly, it is also the main aim of the present inventors to provide a veterinary delivery system for effective absorption into the animal’s vascular system through gastro intestinal tract, having dose delivery accuracy, easy way to administer and shows maximum therapeutic effect.

Keeping this in mind, the present inventors has developed oral film compositions comprising effective amount of Anti-emetic drugs and its pharmaceutically acceptable salts thereof and method of administering the same in treating or preventing Nausea and Vomiting in animals, which are subjected to periodic medications or occasional medications or motion sickness. The major advantages of novel oral film dosage form includes reduced or no difficulty while swallowing, ease of administration, avoid scratches and bites during administration, quick disintegration in the oral cavity besides they are less prone to being spit by the animal.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides oral film of Anti-emetic drugs and its pharmaceutically acceptable salts thereof for veterinary use.

In a preferred embodiment, the present invention provides composition of oral film of Anti-emetic drugs and its pharmaceutically acceptable salts thereof for veterinary use, wherein the composition comprises at least one film forming polymer, plasticizer and one or more pharmaceutically acceptable excipients thereof.

In another embodiment, the present invention provides process for preparing oral film of Anti-emetic drugs and its pharmaceutically acceptable salts thereof for veterinary use, wherein the process may be selected from solvent casting, hot melt extrusion or printing technology.

In another embodiment, the present invention provides oral films of Anti-emetic drugs and its pharmaceutically acceptable salts thereof used for the treatment or prevention of Nausea and vomiting in animals.

DETAILED DESCRIPTION OF THE INVENTION

References in the specification to “one embodiment,” “an embodiment,” “another embodiment,” “a preferred embodiment,” “one aspect,” “another aspect,” “preferred aspect” and the like, indicate that the embodiment described can include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one of ordinary skill in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.

As per United States Pharmacopoeia, Films are classified by the site of application. Accordingly, “Oral films” can be formulated to deliver medication to the mouth such as oral hygiene products or to deliver medication to the gastrointestinal tract for absorption. “Buccal films” and “sublingual films” are formulated to facilitate absorption through the proximal mucosal membranes avoiding first pass metabolism or degradation in the gastrointestinal tract and providing a quick onset of action.

“Oral film” according to the present invention may also referred as “Oral thin film,” “OTF,” “ODF,” “oral drug strip,” “oral strip,” “veterinary oral film”, “oral disintegrating film” or “oral dissolving film”.

The term “veterinary use” according to the present invention includes prevention or treatment of veterinary medical conditions in any animal other than human for which oral films of the present invention find useful. Animals herein unless otherwise specified does not limit to only domestic animals such as cats, dogs, guinea pigs, mice, horses, goats, rabbits, swine, apes, primates, hamsters, ferrets, reptiles, sheep, cows, and other non-human animals for which oral films of the present invention find useful.

The oral film, according to the present invention preferably disintegrates within about five minutes and more preferably within about 180 seconds upon contact with aqueous media or saliva in oral cavity.

An oral film according to the present invention is "non-mucoadhesive" in nature, means that the dosage form is not designed for administration of the active pharmaceutical agent through the oral mucosa i.e. the dosage form is not designed to adhere to the mucosal surfaces of the buccal cavity as an intact film or disintegrated film residue. In particular, the invention provides a non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with aqueous media or saliva in oral cavity of the animal within about five minutes and more preferably within about 180 seconds.

The term “film” according to the present invention includes films, sheets and wafers, in any size and shape, including rectangular, square, or other desired shape. Preferably, they are distinct from pills, tablets, caplets or capsules and wherein the dosage from is like a thin strip of material. The films are generally sufficiently flexible to allow bending or even folding without breaking. The films described herein may be any desired thickness and size such that it may be placed into the oral cavity of the animal. The films may have a thickness of from about 20 microns to about 300 microns. Films may be in a single layer or they may be multi-layered, such as laminated or co-extruded films.

The term “disintegrating” according to present invention is defined as a state in which any residue of the oral film remaining on the screen of the test apparatus known in the art, or in the mouth of animal, is a soft mass having no palpably film core. The disintegration test does not imply complete solution of dosage unit or even of its active constituent, although a dissolved dosage unit would typically be completely disintegrated.

The term “dissolution” according to present invention is defined by the amount of active agent released from the oral film after oral administration or by in-vitro testing known in the art. An in-vitro dissolution test is to evaluate the performance of the product by measuring the amount of active agent dissolved in the dissolution medium. Standardized apparatus known in the art for in-vitro dissolution testing are: USP type I apparatus (basket), USP type II apparatus (Paddle), USP type V apparatus (Paddle over disk).

In one aspect the present invention provides oral film of Anti-emetic drugs and its pharmaceutically acceptable salt thereof for veterinary use.

In another aspect the present invention provides composition and process for preparing oral film of Anti-emetic drugs and its pharmaceutically acceptable salt thereof for veterinary use.

Anti-emetic drugs according to the present invention are selected from the group comprising Maropitant, Aminopentamide, Acepromazine, Promazine and Triflupromazine or any combinations thereof and its pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of Anti-emetic drugs according to the present invention are selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.

Anti-emetic drugs and its pharmaceutically acceptable salts thereof according to the present invention are may be present in an amount of about 0.1% to about 75% by weight based on total weight of the composition.

In one preferred aspect, the present invention provides composition of oral film of Anti-emetic drugs and its pharmaceutically acceptable salt thereof, wherein the composition comprises at least one film forming polymer, plasticizer and one or more pharmaceutically acceptable excipients.

According to the present invention, one or more pharmaceutically acceptable excipients are selected from suspending/thickening agents, fillers/bulking agents, disintegrating agents, stabilizers, surfactants, sweetening agents, taste masking agents, anti-foaming agents, flavoring agents and coloring agents and combinations thereof.

In another aspect, the present invention provides oral film of Anti-emetic drugs and its pharmaceutically acceptable salts thereof comprises one or more film forming polymers. The term “Polymers or Film forming polymers” according to the invention are responsible for imparting adequate mechanical properties to films, and they affect the film disintegration and/or dissolution in oral cavity. Film forming polymers used according to the present invention are not limited to hydrophilic or hydrophobic polymers.

Suitable non-limiting hydrophilic film forming polymers according to the present invention are selected from hydroxypropyl methylcellulose or Hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxy methylcellulose, methyl cellulose, Hydroxypropyl ethylcellulose, povidone, copovidone, polydextrose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, pullulan, sodium alginate, propylene glycol alginate, modified starch, gelatin, pectin, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides, cyclodextrins, galactomannans, Polymerized rosin and combinations thereof.

Suitable non-limiting hydrophobic film forming polymers according to the present invention are selected from ethyl cellulose, Polymethacrylates, polyacrylic acid, methyl methacrylate copolymer, copolymers of acrylic acid and alkyl acrylate, carboxyvinyl copolymers and combinations thereof.

Polymers used according to present invention are available in various viscosity ranges. Depending on the viscosity the quantity of the polymer is chosen.

Film forming polymer/s according to the present invention may be present in an amount of about 10% to about 75% by weight based on total weight of the composition.

In an aspect, the present invention provides oral film of Anti-emetic drugs and its pharmaceutically acceptable salts thereof comprises plasticizers. The term “plasticizers” according to the present invention are responsible for mechanical properties of the film, such as tensile strength and decrease the fragility of film by decreasing the glass transition temperature of polymer. Suitable non-limiting plasticizers according to the present invention are selected from polyethylene glycol, propylene glycol, polyethylene-propylene glycol, glycerol/glycerin, glycerol monoacetate, glycerol diacetate, glycerol triacetate, triacetin, polysorbate, cetyl alcohol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, phthalate derivatives such as dimethyl, diethyl and dibutyl phthalate, citrate derivatives and combinations thereof.

Plasticizers according to the present invention may be present in an amount of about 1% to about 30% by weight based on total weight of the composition.

Suitable suspending/thickening agents according to the present invention are responsible for improving the viscosity of the drug and excipient dispersion preparation and consistency of the oral film. Suitable non-limiting suspending/thickening agents according to the present invention are selected from maltodextrin, natural gums like xanthan gum, carrageen, locust bean gum, cellulose derivatives, dextrin, modified starch and combinations thereof.

Suspending/thickening agents according to the present invention may be present in an amount of about 1% to about 50% by weight based on total weight of the composition.

Suitable filler/bulking agents according to the present invention are selected from Starches, anhydrous lactose, mannitol, Maltodextrin, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, sucrose and combinations thereof.

Disintegrating agents according to the present invention are responsible for quick disintegration of oral film upon contact with aqueous media or saliva in oral cavity. Suitable non-limiting disintegrating agents according to the present invention are selected from Starch, Colloidal silicon dioxide, microcrystalline cellulose, Crospovidone, Sodium Starch glycolate, Croscarmellose sodium and combinations thereof.

“Sweetening agent or Sweetener” according to the present invention enhances the palatable/taste and pleasurable factor, which makes the film relatively acceptable or agreeable to the patient. Suitable non-limiting sweeteners according to the present invention are selected from glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Ammonium Glycyrrhizinate, Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, maltodextrin, xylitol, and the like, hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (Acesulfame-K), and sodium and calcium salts thereof, natural intensive sweeteners, protein based sweeteners such as thaumatoccous danielli (Thaumatin I and II) and combinations thereof.

“Taste masking agents” according to the present invention are responsible for blocking or diminishing the bitter taste of drug substance or excipients present in the film. Suitable non-limiting taste masking agents according to the present invention are selected from ion exchange resins, cyclodextrins and its derivatives, ready made available mixtures of taste mask enhancers and combinations thereof.

Suitable non-limiting buffering agents according to the present invention are selected from sodium carbonate, sodium bicarbonate, Citric Acid, Sodium Citrate, potassium carbonate, potassium bicarbonate, Ammonium Phosphate Dibasic, Sodium Phosphate Dibasic, sodium phosphate tribasic, potassium phosphate dibasic, potassium phosphate tribasic, Borate, calcium carbonate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, aluminium hydroxide, and combinations thereof.

Stabilizers according to the present invention are responsible for improving the shelf life by preventing the degradation of active agents. Suitable non-limiting stabilizers according to the present invention may be selected from Tocopherol, Ascorbic acid, Citric acid, sodium bisulfite, sodium metabisulfite, propyl gallate, Potassium Metabisulfite, butylated hydroxytoluene and butylated hydroxyanisole and combinations thereof.

Suitable non-limiting surfactants according to the present invention are selected from cetyl alcohol, sodium lauryl sulfate, Polyoxyl 40, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 15 hydroxystearate Polysorbate 80, Macrogol stearate, Hydrogenated Castor Oil, Spans®, Tweens®, Ethoxylated oils, poloxamers and combinations thereof.

Suitable anti-foaming agents according to the present invention are selected from simethicone or dimethicone or any agent that removes air bubbles/entrapped air/void from film-forming compositions.

“Flavors” in the present invention are responsible for masking the bitter or nauseating taste of incorporated drug. Suitable non-limiting veterinary acceptable flavoring agents according to the present invention selected from chicken, turkey, beef, pork, lamb, fish, egg, cheese, edible yeast, dairy products which are of either artificially available or naturally available or extracted from meat or organs of animals. Other non-limiting flavoring agents according to the present invention are selected from the group comprising of natural and synthetic flavoring liquids such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, pea nuts and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors. Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin), and combinations thereof.

Suitable coloring agents according to the present invention are selected from the group comprising of food, drug and cosmetic colors (FD and C), drug and cosmetic colors (D and C), or external drug and cosmetic colors (Ext. D and C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Other non-limiting examples of coloring agents according to present invention are selected from known azo dyes, organic or inorganic pigments, or coloring agents of natural origin and combinations thereof.

According to an aspect, some of the excipients used in the oral film of the present invention may have one or more functions i.e. an excipient used in oral fi lm of the present invention may have multi-function like starch and modified starch used in the present invention may also act as a bulking agent and/or disintegrating agent; Maltodextrin used in the present invention may act as a sweetener and/or suspending/thickening agent and/or filler/bulking agent; Mannitol used in the present invention may act as a sweetener and/or as a filler/bulking agent; cellulose derivatives used in the present invention may act as a film forming polymer and/or suspending/thickening agent. Hence, a skilled person should not construe the limit of an excipient stated or illustrated in any aspect or embodiment or an example of oral film in the present invention to a single function.

In a preferred aspect, the present invention provides composition of oral film of Anti-emetic drug(s) and its pharmaceutically acceptable salts thereof for veterinary use, wherein the composition comprises from about 0.1% to about 75% by weight of Anti-emetic drug(s) and its pharmaceutically acceptable salts thereof.

In another preferred aspect, the present invention provides composition of oral film of Anti-emetic drug(s) and its pharmaceutically acceptable salts thereof for veterinary use, wherein the composition comprises:
i. from about 0.1% to about 75% by weight of Anti-emetic drug(s) and its pharmaceutically acceptable salts;
ii. from about 10% to about 75% by weight of at least one film forming polymer;
iii. from about 1% to about 30% by weight of plasticizer; and
iv. one or more pharmaceutically acceptable excipients;
wherein the percentage (%) by weight is relative to the total weight of the composition.

In one aspect, the present invention provides process for preparing oral film of Anti-emetic drugs and its pharmaceutically acceptable salts thereof for veterinary use, wherein the process may be selected from solvent casting, hot melt extrusion or printing technology.

Solvents used according to the present invention in the process for preparing oral film of Anti-emetic drugs or its pharmaceutically acceptable salts thereof may be selected from purified water, a polar organic solvent including, but not limited to ethanol, dichloromethane, isopropanol, acetone, methylene chloride, or any combination thereof.

In one aspect, the present invention provides oral film of Maropitant and its pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides composition of oral film of Maropitant and its pharmaceutically acceptable salt thereof, wherein the composition comprises at least one film forming polymer, plasticizer and one or more pharmaceutically acceptable excipients.

In one aspect, the present invention provides process for preparing oral film of Maropitant and its pharmaceutically acceptable salt thereof, wherein the process may be selected from solvent casting, hot melt extrusion or printing technology.

In a preferred aspect, the present invention provides composition of oral film of Maropitant and its pharmaceutically acceptable salts thereof for veterinary use, wherein the composition comprises from about 0.1% to about 75% by weight of Maropitant and its pharmaceutically acceptable salts thereof.

In another preferred aspect, the present invention provides composition of oral film of Maropitant and its pharmaceutically acceptable salt thereof, wherein the composition comprises:
i. from about 0.1% to about 75% by weight of Maropitant and its pharmaceutically acceptable salts;
ii. from about 10% to about 75% by weight of at least one film forming polymer;
iii. from about 1% to about 30% by weight of plasticizer; and
iv. one or more pharmaceutically acceptable excipients;
wherein the percentage (%) by weight is relative to the total weight of the composition.

In one aspect, the present invention provides composition of oral film of Acepromazine and its pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides composition of oral film of Acepromazine and its pharmaceutically acceptable salt thereof, wherein the composition comprises at least one film forming polymer, plasticizer and one or more pharmaceutically acceptable excipients.

In one aspect, the present invention provides process for preparing oral film of Acepromazine and its pharmaceutically acceptable salt thereof, wherein the process may be selected from solvent casting, hot melt extrusion or printing technology.

In a preferred aspect, the present invention provides composition of oral film of Acepromazine and its pharmaceutically acceptable salts thereof for veterinary use, wherein the composition comprises from about 0.1% to about 75% by weight of Acepromazine and its pharmaceutically acceptable salts thereof.

In another preferred aspect, the present invention provides composition of oral film of Acepromazine and its pharmaceutically acceptable salt thereof, wherein the composition comprises:
i. from about 0.1% to about 75% by weight of Acepromazine and its pharmaceutically acceptable salt;
ii. from about 10% to about 75% by weight of at least one film forming polymer;
iii. from about 1% to about 30% by weight of plasticizer; and
iv. one or more pharmaceutically acceptable excipients;
wherein the percentage (%) by weight is relative to the total weight of the composition.

In another aspect, the present invention provides oral film of Aminopentamide and its pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides composition of oral film of Aminopentamide and its pharmaceutically acceptable salt thereof, wherein the composition comprises at least one film forming polymer, plasticizer and one or more pharmaceutically acceptable excipients.

In one aspect, the present invention provides process for preparing oral film of Aminopentamide and its pharmaceutically acceptable salt thereof, wherein the process may be selected from solvent casting, hot melt extrusion or printing technology.

In a preferred aspect, the present invention provides composition of oral film of Aminopentamide and its pharmaceutically acceptable salts thereof for veterinary use, wherein the composition comprises from about 0.1% to about 75% by weight of Aminopentamide and its pharmaceutically acceptable salt thereof.

In another preferred aspect, the present invention provides composition of oral film of Aminopentamide and its pharmaceutically acceptable salt thereof, wherein the composition comprises:
i. from about 0.1% to about 75% by weight of Aminopentamide and its pharmaceutically acceptable salt;
ii. from about 10% to about 75% by weight of at least one film forming polymer;
iii. from about 1% to about 30% by weight of plasticizer; and
iv. one or more pharmaceutically acceptable excipients;
wherein the percentage (%) by weight is relative to the total weight of the composition.

In one aspect, the present invention provides oral film compositions comprising one or more Anti-emetic drugs and its pharmaceutically acceptable salt thereof used for the treatment or prevention of Nausea and vomiting in animals.

In a preferred aspect, the present invention provides oral film compositions comprising Maropitant and its pharmaceutically acceptable salts thereof used for the treatment or prevention of Nausea and vomiting in animals.

In a preferred aspect, the present invention provides oral film compositions comprising Acepromazine and its pharmaceutically acceptable salt thereof used for the treatment or prevention of Nausea and vomiting in animals.

In a preferred aspect, the present invention provides oral film compositions comprising Aminopentamide and its pharmaceutically acceptable salt thereof used for the treatment or prevention of Nausea and vomiting in animals.

The said invention is further illustrated by following non-limiting examples: which are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Example 1
S. No. Ingredients Quantity per unit (mg)
1 Maropitant Citrate
(equivalent to Maropitant) 40 40 40
2 Hydroxypropyl methylcellulose 40 - 60 - 30 - 50
3 Hydroxypropyl cellulose - 40- 60 10 – 30
4 Microcrystalline Cellulose 5 – 15 15 – 25 15 – 25
5 Polyethylene glycol 4 – 8 4 – 8 4 – 8
6 Glycerin 0 - 12 0 - 12 0 - 12
7 Flavor 4 – 6 4 – 6 4– 6
8 Colorant 0.05 -0.10 0.05 -0.10 0.05 -0.10
9 Dichloromethane q.s - q.s
10 Ethanol q.s q.s q.s
Weight of Film 93.05-141.10 103.05-151.10 103.05-171.10

Brief Manufacturing Procedure:
1. Dispense all the ingredients.
2. Add ethanol in a suitable stainless steel vessel and optionally add dichloromethane.
3. Add Hydroxypropyl methylcellulose and/or Hydroxypropyl cellulose to step 2 under stirring and continue stirring till a homogenous dispersion is obtained.
4. Add Maropitant citrate to the dispersion of step 3 under stirring and continue stirring till a homogenous dispersion is obtained.
5. Add Microcrystalline Cellulose to dispersion of step 4 under stirring and continue stirring till a homogenous dispersion is obtained.
6. Add Polyethylene glycol to dispersion of step 5 under stirring and continue stirring till a homogenous dispersion is obtained.
7. Optionally add Glycerin to dispersion of step 6 under stirring and continue stirring till a homogenous dispersion is obtained.
8. Add colorant to dispersion of step 6/7 under stirring and continue stirring till a homogenous dispersion is obtained.
9. Add flavor to dispersion of step 8 under stirring and continue stirring till a homogenous dispersion is obtained.
10. Homogenize the dispersion of step 9 using a homogenizer to obtain a homogenous dispersion.
11. If any foam observed, de-aerate the dispersion by applying vacuum under slow stirring.
12. The dispersion of step 10/11 is casted using a film casting machine where the dispersion is spreaded on a backing film to form a thin wet film which passed through a drying zone.
13. The dried film is cut into a desired size by using slitter.
14. Pack the film into suitable pouches/sachets
Example 2:
S.No Ingredients Quantity per unit (mg)
1 Acepromazine maleate 25 25
2 Hydroxypropyl methylcellulose 30 - 50 30 - 50
3 Microcrystalline Cellulose 15 – 25 15 – 25
4 Modified starch 10 – 20 10 – 20
5 Polyethylene glycol 4 - 8 4 - 8
6 Gylcerine 0 – 12 0 – 12
7 Polysorbate 80 4 - 8 -
8 Flavor 2 - 4 2 - 4
9 Colorant 0.05 - 0.10 0.05 - 0.10
10 Ethanol q.s q.s
Weight of Film 90.05 -152.10 86.05 -144.10

Brief Manufacturing Procedure:
1. Dispense all the ingredients.
2. Add ethanol in a suitable stainless steel vessel.
3. Add Hydroxypropyl methylcellulose to step 2 under stirring and continue stirring till a homogenous dispersion is obtained.
4. Add modified starch to step 3 under stirring and continue stirring till a homogenous dispersion is obtained.
5. Add Acepromazine maleate to step 4 under stirring and continue stirring till a homogenous dispersion is obtained.
6. Optionally add Polysorbate 80 to dispersion of step 5 under stirring and continue stirring till a homogenous dispersion is obtained.
7. Add Microcrystalline Cellulose to dispersion of step 6 under stirring and continue stirring till a homogenous dispersion is obtained.
8. Add Polyethylene glycol to dispersion of step 7 under stirring and continue stirring till a homogenous dispersion is obtained.
9. Optionally add Glycerin to dispersion of step 8 under stirring and continue stirring till a homogenous dispersion is obtained.
10. Add colorant to dispersion of step 8/9 under stirring and continue stirring till a homogenous dispersion is obtained.
11. Add flavor to dispersion of step 10 under stirring and continue stirring till a homogenous dispersion is obtained.
12. Homogenize the dispersion of step 11 using a homogenizer to obtain a homogenous dispersion.
13. If any foam observed, de-aerate the dispersion by applying vacuum under slow stirring.
14. The dispersion of step 12/13 is casted using a film casting machine where the dispersion is spreaded on a backing film to form a thin wet film which passed through a drying zone.
15. The dried film is cut into a desired size by using slitter.
16. Pack the film into suitable pouches/sachets.

Example 3:
S. No. Ingredients Quantity per unit (mg)
1. Aminopentamide hydrogen sulfate 0.2 0.2 0.2 0.2
2. Hydroxypropyl methylcellulose 20-40 20-40 15-25 15-25
3. Microcrystalline Cellulose 10-15 10 -15 10-15 10-15
4. Modified starch - - 5-10 5-10
5. Polyethylene glycol 2-4 2 - 4 2-4 2-4
6. Gylcerine 0 – 6 0 – 6 0 – 6 0 – 6
7. Polysorbate 80 2- 4 - 4- 8 -
8. Flavor 2- 3 2- 3 1-2 1-2
9. Colorant 0.05 - 0.10 0.05 - 0.10 0.05 - 0.10 0.05 - 0.10
10. Ethanol q.s q.s q.s q.s
11. Purified water q.s q.s q.s q.s
Weight of Film 36.25 -72.30 34.25 - 68.30 37.25 - 70.03 33.25 -62.30

Brief Manufacturing Procedure:
1. Dispense all the ingredients.
2. Mix purified water and ethanol in a suitable stainless steel vessel.
3. Add Hydroxypropyl methylcellulose to step 2 under stirring and continue stirring till a homogenous dispersion is obtained.
4. Optionally add modified starch to step 3 under stirring and continue stirring till a homogenous dispersion is obtained.
5. Add Aminopentamide hydrogen sulfate to step 4 under stirring and continue stirring till a homogenous dispersion is obtained.
6. Optionally add Polysorbate 80 to dispersion of step 5 under stirring and continue stirring till a homogenous dispersion is obtained.
7. Add Microcrystalline Cellulose to dispersion of step 6 under stirring and continue stirring till a homogenous dispersion is obtained.
8. Add Polyethylene glycol to dispersion of step 7 under stirring and continue stirring till a homogenous dispersion is obtained.
9. Optionally add Glycerin to dispersion of step 8 under stirring and continue stirring till a homogenous dispersion is obtained.
10. Add colorant to dispersion of step 8/9 under stirring and continue stirring till a homogenous dispersion is obtained.
11. Add, flavor to dispersion of step 10 under stirring and continue stirring till a homogenous dispersion is obtained.
12. Homogenize the dispersion of step 11 using a homogenizer to obtain a homogenous dispersion.
13. If any foam observed, de-aerate the dispersion by applying vacuum under slow stirring.
14. The dispersion of step 12/13 is casted using a film casting machine where the dispersion is spreaded on a backing film to form a thin wet film which passed through a drying zone.
15. The dried film is cut into a desired size by using slitter.
16. Pack the film into suitable pouches/sachets.
Example 4:
S. No Ingredient Name % w/w mg/ unit
1 Maropitant Citrate 42.11 40.00
2 Hypromellose E15 36.84 35.00
3 Microcrystalline cellulose 10.53 10.00
4 Polyethylene glycol 6000 (PEG) 5.26 5.00
5 Glycerine 2.11 2.00
6 Flavor (Tuna Salmon fish) 3.16 3.00
7 Dichloromethane QS QS
8 Ethanol QS QS
Film weight (mg) 100.00 95.00

Brief Manufacturing Procedure:
1. Mix the solvents Dichloromethane and ethanol in a suitable stainless steel vessel.
2. Added Maropitant Citrate to the solution of step 1 and stirred with a suitable stirrer to get a homogenous dispersion.
3. Added Hypromellose E15 to step 2 under stirring and continue stirring till a homogenous dispersion is obtained.
4. Added Glycerin to dispersion of step 3 under stirring and continue stirring till a homogenous dispersion is obtained.
5. Added PEG to dispersion of step 4 under stirring and continue stirring till a homogenous dispersion is obtained.
6. Added Microcrystalline cellulose to step 5 under stirring and continue stirring till a homogenous dispersion is obtained.
7. Added flavor to dispersion of step 6 under stirring and continue stirring till a homogenous dispersion is obtained.
8. The suspension was homogenized using a homogenizer to obtain a homogenous dispersion.
9. De-aerated the dispersion by applying vacuum under slow stirring.
10. The dispersion is casted using a film casting machine where the dispersion is spreaded on a backing film to form a thin wet film which passed through a drying zone.
11. The dried film is cut into a desired size by using slitter.
12. Pack the film into suitable pouches/sachets
Disintegration study: The obtained oral film of Example 4 is tested for disintegration test using static method, where the oral film is placed in a petri dish containing water and the time taken for disintegration is observed.
• Time taken for disintegration - 60 seconds
Dissolution: Also the obtained film of Example 4 is tested for dissolution in USP type 5 (Paddle over Disc) apparatus, 900ml volume, 75rpm using pH 7.2 Phosphate buffer as dissolution medium and the results are given below:

Time (minutes) % Cumulative drug dissolved
5 77
10 80
15 94

Form the above result, the oral film of present invention has shown more than 90% of drug is released within 15 minutes.
Therefore, oral films of the present invention formulated according to an embodiment has shown quick disintegration and dissolution of drug, which solves the problems mentioned above like difficulty of administration, swallowing, dosing errors etc in animals.
,CLAIMS:We claim:

1. An oral film of Anti-emetic drug(s) and its pharmaceutically acceptable salt thereof for veterinary use.

2. The oral film as claimed in claim 1, wherein the Anti-emetic drug(s) is selected from Maropitant, Aminopentamide, Acepromazine, Promazine, Triflupromazine and combinations thereof and its pharmaceutically acceptable salt thereof.

3. The oral film as claimed in claim 1, wherein the film comprises:
a. Anti-emetic drug(s) and its pharmaceutically acceptable salt thereof selected from Maropitant, Aminopentamide, Acepromazine, Promazine, Triflupromazine and combinations thereof;
b. at least one film forming polymer;
c. plasticizer; and
d. one or more pharmaceutically acceptable excipients.

4. The oral film as claimed in claim 3, wherein the film forming polymer is selected hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxy methylcellulose, methyl cellulose, Hydroxypropyl ethylcellulose, povidone, copovidone, polydextrose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, pullulan, sodium alginate, propylene glycol alginate, modified starch, gelatin, pectin, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides, cyclodextrins, galactomannans, polymerized rosin, ethyl cellulose, Polymethacrylates, polyacrylic acid, methyl methacrylate copolymer, copolymers of acrylic acid and alkyl acrylate, carboxyvinyl copolymers and combinations thereof.

5. The oral film as claimed in claim 3, wherein the plasticizer is selected from polyethylene glycol, propylene glycol, polyethylene-propylene glycol, glycerin, glycerol monoacetate, glycerol diacetate, glycerol triacetate, triacetin, polysorbate, cetyl alcohol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate and combinations thereof.

6. The oral film as claimed in claim 3, wherein one or more pharmaceutically acceptable excipients are selected from suspending/thickening agents, disintegrating agents, fillers/bulking agents, stabilizers, surfactants, sweetening agents, taste masking agents, buffering agents, anti-foaming agents, flavoring agents, and coloring agents.

7. The oral film as claimed in claims 1 and 3, wherein the process of preparing oral film of Anti-emetic drug(s) and its pharmaceutically acceptable salt thereof is by solvent casting, hot melt extrusion or printing technology thereof.

8. The oral film as claimed in claims 1 and 3, wherein the oral film of Anti-emetic drug(s) and its pharmaceutically acceptable salt thereof is administered to any non-human animal for the treatment or prevention of Nausea and vomiting.