WO2018122867A1

WO2018122867A1 - Thin film formulations of 4-diphenylmethyl-1-piperazine derivatives and their salts

Info

Publication number: WO2018122867A1
Application number: PCT/IN2017/050613
Authority: WO
Inventors: Anwar Siraj DAUD; Nidhi Prakash SAPKAL; Minal Nandkumar BONDE; Shikha BARVE
Original assignee: Zim Laboratories Limited
Priority date: 2016-12-27
Filing date: 2017-12-22
Publication date: 2018-07-05
Also published as: EP3562475A4; EP3562475A1

Abstract

This invention comprises a stable oral dispersible thin film and a process of making the same, the film comprising a 4-Diphenylmethyl-1-piperazinyl derivative or its pharmaceutically acceptable salts; characterized by, during storage of the film, level of the individual impurities arising out of degradation of the 4-Diphenylmethyl-1-piperazinyl derivative or its pharmaceutically acceptable salts not exceeding 1% of the added drug, and total impurities not exceeding 2% and the taste is not less than "acceptable" when scored by a taste panel on a scale of Excellent (5), Pleasant (4), Acceptable (3), Bitter (2) and Extremely bitter (1). The film is also thin, translucent, non-curving, non-tacky and flexible with folding endurance of 25 or more, dissolution not less than 75% in 45 minute. The process comprises a step of adding sodium hydroxide before the film casting is done, selecting temperature range for drying step of the film appropriate for getting a stable film, and adding plasticizer/s.

Description

THIN FIL M FOR MU LATIO NS O F 4-DIP H E NY L MET HY L-1 -PIP E RAZINE

DE RIVATIV E S AND T H E IR SALTS

TE C H NICAL FIE L D

The present invention relates to stable thin film formulations of 4-Diphenylmethyl- 1 -piperazine derivatives and their salts and process of manufacturing thereof.

¾

DE S C RIPTIO N O F T H E INV E NTIO N

Known treatment of allergic rhinitis, hay fever, angioedema, urticarial etc. includes 4-Diphenylmethyl-1 -piperazinyl derivatives and their salts. T hey are effective histamine H1 receptor antagonists. Buclizine, cyclizine, Meclizine, ft, Oxatomide, Hydroxizine, C etirizine and levocetirizine are members of this class of molecules. P resence of piperazine nitrogen makes them basic in nature.

P referred forms of these molecules for the development of various formulations are their salts; which include, without limitation, hydrochloride, dihydrochloride. citrate, palmoate and the like. Tablets (including chewable tablets, orally ¾ disintegrating tablets), syrups, solutions, drops etc. are the conventional dosage forms for adults and children available in the market.

Tablets and liquid formulations have several limitations as dosage forms. In situations where swallowing is a problem or the pharmaceutical agent cannot &\ efficiently pass through barriers in gastrointestinal tract, tablets is not an appropriate dosage form. It is challenging to administer chewable tablets and orally disintegrating tablets to children, mentally cha llenged, nauseated, unconscious, and elderly patients. F urther, orally disintegrating tablets can be made only if equipment for lyophilization or compression at low pressure process is available and have to be used as per special instructions of handling and administration only because of their extreme friable nature. Limitations of liquid formulations is that administration of precise dose is not possible to non- cooperative patients; further, more care in handling and space is required during transport & storage.

S olution to above limitations of tablets and liquid formulations is provided by Oral dispersible films. T hin films have succeeded to enhance patient compliance for several pharmaceutical active ingredients. However, there are problems in making orally dissolvable films from 4- Diphenylmethyl-1 -piperazinyl derivatives and their salts because they tend to degrade in the presence of moisture, heat, hydrogen ions and oxygen conditions prevailing during process of making films and during further storage; resulting in

¾ the loss of strength and generation of unwanted impurities. When formulated in the form of tablets, generally dry granulation or direct compression is preferred for these derivatives so as to avoid the use of vulnerable moisture and temperature conditions. In the formulation of liquid dosage forms heat is avoided. Thus, tablet and liquid formulations remain stable throughout the shelf life. ft, However, in making a thin film, above factors catalyzing the degradation cannot be avoided.

Still further, ideal technology for the formulation of thin films should produce thin, flexible films with pleasa nt taste, desired disintegration and dissolution profiles. These films should maintain their physical characteristics and chemical stability ¾ during manufacturing, storage and transportation. Developing thin film formulations for various active ingredients consists of many challenges. While some pharmaceutical products based on this technology are already in the market, but researchers are experiencing difficulties in developing more and more active ingredients into this dosage form because of the issues like loading, &\ physical stability, chemical stability, taste, desired release profile etc. Making thin films from 4-Diphenylmethyl-1 -piperazinyl derivatives has to overcome all these problems and also mask their unpleasant bitter taste.

Additionally, members of the class of 4-Diphenylmethyl-1 -piperazinylderivatives and their salts have varying solubility, are bitter in taste and exhibit chemical instability in the presence of moisture and heat. Most importantly these molecules are prone for chemical degradation during the manufacturing process typically used for manufacturing of oral thin films where film forming polymers are hydrophilic, solvent is generally water and films are dried using the heat. T he final dosage form has more water than is present in tablets. All these are risk factors that lead to chemical degradation of 4-Diphenylmethyl-1 -piperazine derivatives during manufacturing of thin films containing them and during storage of such films. When a drug degrades into other chemical forms they add up to the load of chemical impurities. Various pharmacopoeia prescribe limits for these chemical impurities individually and also for the sum total of all the impurities. T he limit for ¾ individual impurities may vary from case to case within a range of 0.2% to 1.0% for P iperazinyl derivatives and for total impurity it may vary from 1 % to 2 %. During the shelf life of the product, the impurities should be within the prescribed limit for regulatory purpose for human/Veterinary use. ft, Objective of the present invention is to work out a process of formulation of bitter- less thin films of acceptable stability comprising 4-Diphenylmethyl-1 -piperazinyl derivatives and their salts.

S U MMARY O F T HE INVE NTIO N

The invention comprises a stable oral dispersible thin film comprising a 4- Diphenylmethyl-1 -piperazinyl derivative or its pharmaceutically acceptable salts. The stability is characterized by: (a) during storage of the film, level of the individual impurities arising out of degradation of the 4-Diphenylmethyl-1 - &\ piperazinyl derivative or its pharmaceutically acceptable salts does not exceed 1 % of the added drug, (b) total impurities does not exceed 2% of the added 4- Diphenylmethyl-1 -piperazinyl derivative or its pharmaceutically acceptable salts; and (c) the taste is not less than acceptable_, when scored by a taste panel on a scale of Excellent (5), P leasant (4), Acceptable (3), Bitter (2) and Extremely bitter (1 ). T he stable oral dispersible thin film according to this invention is also thin, translucent, non-curving, non-tacky and flexible with folding endurance of 25 or more, dissolution not less than 75% in 45 minute, individual impurity not more than 1 % and total impurity not more than 2%. The stable oral dispersible thin film according to this invention further comprises one or more of (i) one more water soluble film-forming polymer/s, (ii) one or more water-insoluble film forming polymers, (iii) one or more stabilizer/s, (iv) one or more plasticizer/s, (v) one or more flavouring agents, (vi) one or more sweetening ¾ agent s, (vii) one or more taste masking agents, (viii) optionally surfactant s, and other optional one or more pharmaceutically acceptable excipients or mixtures thereof.

The 4-Diphenylmethyl-1 -piperazinyl derivative or its pharmaceutically acceptable salts comprises either Levocetirizine dihydrochloride or cetirizine ft, dihydrochloride.

This invention also comprises a process for making stable oral dispersible thin film comprising a 4-Diphenylmethyl-1 -piperazinyl derivative or physiologically acceptable salts thereof; the process comprising following steps: (a) adding sodium hydroxide before the film casting is done in an amount appropriate for ¾ providing stability to the film, (b) selecting temperature range for drying step of the film appropriate for getting a stable film, and (c) adding plasticizer/s in amount appropriate for overcoming effects of chemicals adverse to the folding endurance of at least 25. T he folding endurance of oral dispersible thin film is the number of times the film can repeatedly folded at the same place till the film/strip breaks. &\ The 4-Diphenylmethyl-1 -piperazinyl derivative or physiologically acceptable salts, used in this invention for making the stable oral dispersible thin film, comprises Buclizine, cyclizine, Meclizine, Oxatomide, Hydroxizine, C etirizine and levocetirizine DETAIL E D DE S C R IPTIO N OF T H E INVE NTIO N

C etirizine and Levocetirizine are chosen as representatives of 4-Diphenylmethyl- 1 -piperazinyl derivatives to work out a process for making acceptably stable oral ¾ thin films for delivery of these derivatives to patients in need of them. S ince the chemistry of all these derivatives is basically same, all the members of this group can be considered as a Markush group; and whatever works with cetirizine and Levocetirizine shall work for other 4-Diphenylmethyl-1 -piperazinyl derivatives and their salts too.

Levocetirizine is a third-generation non-sedative antihistamine, the active R- enantiomer developed from the second-generation antihistamine C etirizine. Levocetirizine, an inverse agonist decreases activity at histamine H1 receptors and thereby prevents the release of other allergy chemicals and increased blood

¾ supply to the area. T he typical symptoms of hay fever get relieved on account of this mechanism with more effective with fewer side effects than the second- generation drugs. It does not prevent the actual release of histamine from mast cells. .Levocetirizine dihydrochloride is acknowledged for relief of symptoms associated with seasonal and perennial allergic rhinitis, and for treatment of

1&\ uncomplicated skin manifestations of chronic idiopathic urticaria.

The chemical name of the marketed Dihydrochloride salt of Levocetirizine is (R)- [2-[4-[(4-chlorophenyl) phenylmethyl]-1 -piperazinyl] ethoxy] acetic acid dihydrochloride. The molecular weight of Levocetirizine dihydrochloride is about t& 461.82 and its molecular formula is C₂i H₂₅C IN₂0₃.2HC I.

Levocetirizine, optionally in the form of a pharmaceutically acceptable salt such as the dihydrochloride salt, is described in US patent No. 4525358. Levocetirizine dihydrochloride is available as a oral tablet or as an oral solution

When incorporated in a film, these compounds tend to undergo degradation during process of making the film as well as under storage conditions on account of heat, oxidant, moisture and variations in pH in such films and contributes to increasing level of impurity during storage.

The Indian patent application No. 684/MU M/2007 (hereinafter ΙΝ Έ84) discloses ¾ ease and rapid dissolution and of bitter taste masking in form of strips or thin films of C etirizine dihydrochloride and a process for its preparation. However, film or strips disclosed in IN ^'584 mainly focus on ease and rapid dissolution and of bitter taste masking in form of strips or thin films and a process for its preparation; and does not provide method on how to prevent instability of the ft, drug in the strips.

An Indian patent application IN 4385/C H E/2012 (hereafter IN 385) discloses a novel porous laminate drug delivery system; said system comprises a layer/layers of film comprising an active ingredient(s) or in combination and at ¾ least one pharmaceutically acceptable excipient. Levocetirizine is listed/claimed as one of the active ingredients that can be used in the said delivery system.

Another Indian patent application 4775/C H E/2012(hereinafter :775) discloses relates to entrapment of drug in dummy/drug loaded delivery systems and its &\ associated coatingsAreatments, its processes and the equipments for preparing the same. Levocetirizine is one of the drugs that can be loaded in this system.

791 /C H E /201 1 discloses a mucoadhesive polymer film comprising a core comprising at least one active ingredient and at least one pharmaceutically acceptable excipient, wherein said core comprises a coated portion and an uncoated base portion, and wherein said coated portion comprises at least one layer of a polymeric coat. This system contemplates Levocetirizine as one of the active ingredients which can be delivered through such a film. US 9,393,218 has disclosed film-forming polyurethanes that are used in hair care agents or mixtures of these polyurethanes with other polymers in pharmaceutical preparations for dermal or transdermal administration of active ingredients, as well as patches and pharmaceutical preparations that contain these hair care polyurethanes. P harmaceutical preparations not containing the film-forming polyurethanes are excluded from the scope of this invention. C etirizine is one of the active agents that are stated to be eligible for use in such films. F urther, these patched are for dermal or transdermal delivery of active agent, not for trans- mucosal delivery; they are skin patch wherein said patch has a wearing time of at ¾ least 24 hours. Still further, the stability problems of C etirizine are not addressed to in this invention.

US 9265757, US 8920837, US 6569463, US 6605302, US 6923988, US 20030044457, US 2003021 1 136, US 2003021 1 136, US 2003021 5496, 3 US 201 10237563, US 20120156229, have all disclosed films in which cetirizine is mentioned as one of the active ingredients that can be used for various aspect of respective invention, however, none of them address the issue of instability of C etirizine while making a thin film for oral or mucosal delivery.

¾ US 6,171 ,618 discloses a film carrying C eterizine, but it is not an oral thin film; it comprises a sustained release core comprising pseudoephedrine, with an immediate release layer comprising cetirizine and a water soluble film forming polymer.

1&\ US 20060127473 discloses a pharmaceutical composition comprising at least one active pharmaceutical ingredient in a pharmaceutically effective amount and silicified microcrystalline cellulose in a stabilizing effective amount. One of the pharmaceutical composition is disclosed as film of C etirizine.

US 20060127473 discloses a pharmaceutical composition comprising at least one active pharmaceutical ingredient in a pharmaceutically effective amount and silicified microcrystalline cellulose in a stabilizing effective amount. T he pharmaceutical ingredients covered within the scope of this invention are considered to be those who oxygen sensitive during storage. A film is claimed only for a pharmaceutical composition comprising phenylephrine. Cetirizine is envisaged as one of the pharmaceutical ingredients which can be stabilized in this way. However, no enabled example of C etirizine films made in this way are provided and no information is available of the extent of stabilization achieved in this way. However, in general, silicified microcrystalline cellulose interferes with the formulation of good quality films when used in the quantities as claimed in US 20060127473 for the film preparation, did not permit formation of good films and could not contribute to the stability of drug.

¾ US 20080020024 has claimed within its scope oral films containing cetirizine.

However, the invention relates to a consumable film that contains ^"P U R E - C OT E .™. B793_., a modified starch as one of the essential ingredients and does not relate to problems in stability of oral films containing Cetirizine E xamples are provided for Dextromethorphan H Br; no example is provided for C etirizine.

J P2012197266 has disclosed a stable formulation blended with cetirizine hydrochloride and tranexamic acid. S O LUTIO N: The pharmaceutical composition includes (A) to (C): (A) cetirizine hydrochloride; (B) tranexamic acid; and (C) one or more kinds of colored stabilizers selected from the group consisting of

¾ riboflavin, sodium riboflavin phosphate, riboflavin tetrabutyrate and hesperidin.

The problem to be solved comprises to provide a stable formulation blended with cetirizine hydrochloride and tranexamic acid. The pharmaceutical composition, the solution to above problem, includes (A) to (C): (A) cetirizine hydrochloride; (B) tranexamic acid; and (C) one or more kinds of colored stabilizers selected from

1&\ the group consisting of riboflavin, sodium riboflavin phosphate, riboflavin tetrabutyrate and hesperidin. T hus, the problem to be solved is stability of formulation blended with cetirizine hydrochloride and tranexamic acid; and does not relate to problem of stability of cetirizine hydrochloride containing oral film. C N102133179 has disclosed a stable cetirizine oral solution. E ach 1000ml of the cetirizine oral solution contains 1 g of cetirizine hydrochloride, 80-100g of propylene glycol and 360-400g of sorbitol. The oral solution has a simple formula, few kinds of auxiliary materials and good stability. However, oral solutions are not faced with factors such as drying at high temperature, more extensive exposure to oxygen while drying the film stored etc. That lead to problems of instability of C eterizine in an oral film.

C N101491524 has disclosed an oral preparation composition prepared by being matched with an alkaline compound taken as a stabilizing agent in cetirizine. T he stability of an oral preparation added with the stabilizing agent is greatly improved. A method of improving the stability of the West C innarizine formulations for pharmaceutical composition is disclosed, the composition comprises C etirizine or a pharmaceutically on C innarizine acceptable salt thereof and at least one basic compound as a stabilizer. The basic compound used as ¾ stabilizer used is a basic compound, such as carbonate, bicarbonate or a hydroxide and the oral preparation illustrated is a tablet. No illustration is provided for oral films which are more susceptible to the instability of C etirizine because of the manufacturing processes. ft, Thus, there is no prior art which has taken into consideration the problem of instability of C etirizine in making the film and the prior art publications which disclose films containing Cetirizine do not take into consideration overcoming the problem of degradation of Cetirizine and Levociterizine that is known to occur under the conditions that are used in making these films. F urther, these prior art¾ methods often require specialized equipment employ mixtures of several excipients. Despite the wide existence of oral films in the prior art there is a still need for providing improved/stable oral film that is easy to make and that can stably accommodate 4-Diphenylmethyl-1 -piperazinyl derivatives and their salts and also overcome the bitterness of these derivatives.

Therefore, an object of the present disclosure is to provide a composition for preparing a bitterless oral dispersible film comprising 4-diphenylmethyl-1 - piperazine derivatives and/or pharmaceutically acceptable salts thereof, and minimizing degradation of active ingredients.

The present invention discloses a stable oral dispersible film comprising a 4- diphenylmethyl-1 -piperazine derivative or its pharmaceutically acceptable salt thereof; and a method of preparing the same as exemplified/illustrated by derivatives of Levocetirizine and C eterizine. Levocetirizine has chemistry broadly similar to the group 4-diphenylmethyl-1 -piperazine derivatives and strategies to make it stable in a film shall be applicable to all the members of this group of derivatives. In one embodiment of this invention the bitter taste of thin films containing 4- diphenylmethyl-1 -piperazine derivatives was masked using ion exchange resin; the quantity of the ion exchange resin used is such that it does not affect the physical properties of films like flexibility, instant wettability, non curving and non- ¾ tacky nature. Polacrilin Potassium has been used as an illustration of ion exchange resin herein. Any other ion exchange resin may be used in this case.

In one embodiment of this invention, the process of making the film comprises a step of adding sodium hydroxide in an amount that provides stability to the film. ft, In another embodiment of this invention, The process of making the film comprises selection of appropriate temperature during drying step of the film.

In view of the fact that the process of film making involves several factors that are known to be detrimental to the stability of 4-diphenylmethyl-1 -piperazine ¾ derivatives or their salts, surprisingly an orally dissolving film containing 4- diphenylmethyl-1 -piperazine derivatives or their salts; as represented by C etirizine and Levocetirizine, having better chemical stability during storage, good solubility, breakage prevention, flexibility/folding endurance of the film in the course of manufacturing process, handling, storage and distribution could be &\ made. In one aspect this invention comprises use of plasticizers in optimum proportion to overcome the adverse effect of chemicals that affect the physical properties of the film such as folda bility. P ropylene glycol and glycerine have been used as illustrative plasticizers; which can be replaced with many other plastcizers that would give the effect of maintaining folda bility of the film.

The oral dispersible film of C etirizine and Levocitetrizine or its pharmaceutically acceptable salt made by process of this invention remained stable under IC H (International Council on Harmonisation of Technical R equirements for R egistration of P harmaceuticals for Human Use) guidelines.

For the purpose of this specification, the meaning of certain terms have been defined during the course of description, wherever appropriate. The term about_, when used in the context of a clinical parameter or a property that is expressed in a numerical scale or numerical description, e.g., pH, temperature, amount, concentration, and molecular weight, indicates there is a range, which is not limited by specific numerals, but it is also not indefinite in its ¾ coverage since it includes variation on both sides of the numeral specified therein only to the extent that is considered reasonable by a person skilled in the art to the context in which the term about_, is used. For example, if heating of a film is stipulated to be adjusted to about_, or around_, 50° C for getting a stable film, it does not indicate any indefiniteness but includes all temperatures on both sides ft, of 50° C upto which one can dry the film and acceptable level of stability will be obtained and definitely excluding drying temperatures which shall not yield a film of acceptable stability. The term about_, or around_, in this case is pertinent because in such cases the transition from acceptable to unacceptable temperature is gradual and pin-pointedly identifying the end points for a person ¾ skilled in the art to practice that step shall be unrealistic.

As used herein, the singular form a _,, an_, and ^"the _, include also the plural references and plural references include singular references unless the context clearly dictates otherwise. For example, the term a pharmaceutically acceptable &\ salt_, includes a plurality of pharmaceutically acceptable salts, including combination thereof; and a term ^"derivatives _, includes a single derivative too.

As used herein, ^"stable_, or ^"stabilizing_, refers to the Active P harmaceutical Ingredient (API) in a composition remaining so much stable that it remains pharmaceutically efficacious for its intended use during storage period. Usually, the market requirement is that the film should remain stable for 24 months to 36 months. In the instant case, the API comprise members of the class of 4- Diphenylmethyl-1 -piperazinyl derivatives and their salts. C eteirizine or Levoceteirizine or their pharmaceutically acceptable salt s thereof represent this class, as a pharmaceutically active ingredient that is targeted to be stable in orally dissolving films and such films are targeted to meet the standard set by relevant regulatory agency, including the United S tates Food and Drug Administration, for use of such films as dosage forms for this medicament. Thus, a composition regarded as ^"stable _, may comprise certain minor degree of degradation of one or more ingredients, so long as the degree of degradation does not make it unusable for its intended use, e.g. does not fall below the standard for use as a medicament. For the purpose of this specification, the standard proposed for acceptable level of impurities is that the individual ¾ impurities arising out of degradation of these drugs should not be more than 1 % of the added drug and total impurity from more than one impurity thus formed should not be more than 2 % of the added drug.).

The present invention relates to stable oral dispersible film comprising a 4- ft, Diphenylmethyl-1 -piperazinyl derivative or its salts as active ingredient and one or more pharmaceutically acceptable excipients or combination thereof.

In one embodiment the present invention is illustrated by making a stable film from Levocetirizine dihydrochloride and cetirizine dihydrochloride.

In certain embodiments of this invention, one or more pharmaceutically acceptable excipients or mixtures thereof includes, one or more of (i) film-forming polymer/s or combination thereof, (ii) stabilizer/s or combination thereof, (iii) plasticizer/s or combination thereof, (iv) flavoring and sweetening agent s, &\ optionally surfactant/s, taste masking agent s and other excipients.

The examples of film forming polymer include but are not limited to water-soluble film forming polymers or water-soluble film forming polymers in combination with water-insoluble polymers. The examples of Water-soluble film forming polymers, include without limitation, cellulose derivatives containing hydrophilic groups, such as cellulose, cellulose derivatives, cellulose ethers likehydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose (Na-C MC), starch and derivatives thereof e.g., maltodextrins, pullulan, gelatin, G ums like, gum acacia, gum arabic, tragacanth, guar, xanthangumetc, pectin, chitosan, chitosan derivatives, dextran, carrageenan, hyaluronic acid), polyalkylene oxides, polyalkylene glycols, polyethylene glycol (P E G ), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyacrylic acid, divinyl ether-maleic anhydride, polyphosphazene, polyphosphates, polyphosphonates, poly(2-alkyl-2- oxazolines), N-(2-hydroxypropyl) methacrylamide, and polyacrylamide, or combination thereof.

Water-insoluble polymers as carriers for a drug for making a film include, but are ¾ not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, acrylic polymers (e.g., methacrylate copolymer, methyl methacrylate-diethylaminoethyl methacrylate copolymer), polyvinyl acetate, sodium sulphonated polyesters, carboxylated acrylics and shellac or combinations thereof and the like. T he physiochemical ft, properties and nature of film forming polymers can be varied without departing from the spirit of this invention. In preferred embodiments, the film forming polymer is comprised of 15- 85 wt% based on total solid content of the film.

The term "stabilizing agent" refers to a pharmaceutically acceptable excipient that ¾ enhances the chemical or physical stability of the active ingredient in the formulation. In preferred embodiments, the amount of stabilizing agent in the composition may range from about 0.01 % to about 25% by weight of the Levocetirizine or salts thereof. &\ The example of stabilizer(s) includes one or more of an anti-oxidant s, a pH modifier/s, a chelating agent s, a preservative/s, a buffering agent or combination thereof. T he stabilizer(s) may be present alone or in combination with others in different proportions.

An anti-oxidant may also be added to the film to prevent the degradation of an active ingredient, especially where the active ingredient is photosensitive or susceptible to reacting with oxygen on contact of air. The examples of antioxidants include but are not limited to -Tocopherol (Vitamin E ), B HA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), sesamol, lecithin, Ascorbic acid (Vitamin C), G lutathione, Lipoic acid, gallates, resveratrol, polyphenols (e.g. ubiquinone, or coenzyme Q 10), polyene compounds (e.g. ^-C arotene), ethyl hydrocaffeate, nor-dihydroguaiaretic acid, gentisic acid ethanolamine or combination thereof. In certain embodiments, preservatives may be added to the film composition to maintain stability of the formulation ingredients during shelf storage, the examples of preservative include, without limitation, parabens, derivatives of parabens, benzyl alcohol, quaternary ammonium halides, phenylcarbinol, ¾ thimerosal, sodium benzoate, sorbic acid, salts of sorbic acid, propionic acid, salts of propionic acid, acetic acid, salts of acetic acid, citric acid, or combination thereof and alike. These are only exemplary. Other preservative compounds known to those skilled in the art may also be used. ft, In certain embodiments, buffers may be added to the film formulations, Buffering agents can be added to manipulate the pH. The pH is involved in the dissolution and stabilization of the components in the formulation, and also with their absorption through the oral mucosa. T he examples of buffering agent include but are not limited to borate buffers, tartarate buffers, lactate buffers, citrate buffers,¾ phosphate buffers (e.g. potassium phosphate monobasic), citric acid/phosphate buffers, carbonate/carbonic acid buffers, succinate/succinic acid buffers, and tris(hydroxymethyl) aminomethane /hydrochloric acid buffers or combination thereof. In preferred embodiments, the buffer system represents about 0% to about 15% by weight of the film.

In embodiments of this invention, plasticizers are added to the film formulations to provide appropriate flexibility and physical properties to the film. The examples of plasticizer include but not limited to glycerin, glycerol oleate, medium chain fatty acid, polyethylene glycol, propylene glycol, propylene glycol monocaprylate, propylene glycol dicaprylate, saccharide, sugar alcohols and triacetin. More preferable plasticizers comprise glycerin or propylene glycol or combination thereof. In the preferred embodiments, the plasticizer is comprised of 0.5-40 wt% based on total solid content of the film. In embodiments of this invention, surfactants are added to the film formulations to obtain the homogeneous casting dispersions and to provide appropriate wettability to the films. T he examples of surfactant include, without limitation, sodium lauryl sulfate, mono and diglycerides of fatty acids and polyoxyethylene sorbitol esters, such as polyoxyethylene (20) sorbitan monostearate (Polysorbate 60) and polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), derivatives thereof, sodium salt of the monsulfated monoglyceride of hydrogenated coconut oil fatty acids; cocamidopropylbetaine or combination thereof. T he surfactants may function as wetting agent In the preferred embodiments, the surfactant is ¾ comprised of 0.1 -10 wt% based on total solid content of the film.

In embodiments of this invention, organoleptic additives like flavouring agents, sweetening agents, saliva stimulating agents, taste masking agents, colouring agents are added to the film formulations to impart acceptable organoleptic and ft, aesthetic properties to the films. The examples of flavoring agent include but not limited to Menthol, cherry menthol, orange flavor, natural raspberry, spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. T hese flavour agents can be used individually or combination thereof. In the preferred embodiments, the flavouring ¾ agent is comprised of 0.2-5 wt% based on total solid content of the film.

Bitter masking agents are added in the mixture prepared for casting the film to mask the bitterness of the 4-Diphenylmethyl-1 -piperazinyl derivatives. In illustrated examples Polacrilin Potassium, availa ble in the market under Trade &\ name as Kyron™ T-134 is used as a weakly acidic potassium form cation exchange resin as well as bitterness masker. However, this may be replaced with other bitterness masker of similar efficacy.

The examples of sweetening agent include but are not limited to (a) monosaccharides such as glucose (dextrose), fructose (levulose), galactose, (b) dextrose derivatives, dextrin, dextrin derivatives such as maltodextrin, (c) disaccharides such as sucrose, maltose, lactose and cellobiose or combination thereof. Additional examples of natural sweeteners include polysaccharides such as amylose and amylo pectin. F urther examples of natural sweeteners include xylose, ribose, mannose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin. S till further examples of sweeteners includes C rystalline hydrate forming sugars, which include isomalt trehalose, and raffmose, or combination thereof and alike. E xamples of artificial high intensity sweeteners include, without limitation, aspartame, neotame, saccharine, Acesulfame-K, cyclamate or combination thereof. In the preferred embodiments, the sweetening agent is comprised 0.1 -20 wt% based on total solid content of the film,

¾

The examples of flavors that can be used in making the films include, without limitation, Lemon flavor, grape flavor, lime flavor, vanilla flavor, chocolate flavor, clove flavor, peppermint flavor, apple flavor, pear flavor, pineapple flavor, peach flavor, apricot flavor, strawberry flavor, butter scotch flavor, mix fruit flavor, ft, raspberry flavor, cherry flavor, prune flavor, cinnamon flavor, nutmeg flavor, coffee flavor, orange flavor, mango flavor, orange booster, raspberry flavor, papaya flavor, banana flavor and milk powder flavor.

In certain embodiments, the film comprises taste-masking agents. Taste-masking ¾ agents can be added to ameliorate the organoleptic characteristics of the orodispersible or transmucosal film.

In certain embodiments, taste masking agents may be used to mask unpleasant taste of some components. Exemplary of taste-masking agents include, but are &\ not limited to, cyclodextrins, maltodextrins, ion-exchange resins (Kyron), amino acids, simethicone, E udragit S 100, gelatin, monoaminoglycerrhizinate, gelatinized starch, liposomes, lecithins or lecithin-like substances and salts. In preferred embodiments, the taste masking agent comprises about 0% to about 15% based on the dry weight of all the components of the film. In the preferred embodiments, the taste masking agent is comprised of 0.1 -5 wt% based on total solid content of the film.

The examples of colouring agent include but not limited to pigments, dyes, natural food colors that are suitable for food and drug applications, such as F D&C coloring agents, sunset yellow color or combination thereof. In the preferred embodiments, the colouring agent is comprised of 0.01 -1 wt% based on total solid content of the film. The examples of saliva stimulating agent include but not limited to phosphoric acid, adipic acid, succinic acid, citric acid, malic acid, tartaric acid, fumaric acid, lactic acid, acetic acid, sorbic acid, cinnamic acid or combination thereof. In preferred embodiments, a saliva stimulant represents about 0% to about 10% ¾ based on the dry weight of all the components of the film.

In embodiments of this invention, an opacifier may be added to the film formulation. T he examples of opacifier include but not limited to titanium dioxide and its derivative or combination thereof.

In embodiments of this invention, an anti-tacking agent may be added to the film formulation. T he examples of anti-tacking agent include but not limited to silicon dioxide (Aerosil), talc or combination thereof.

¾ Optionally, an anti-foaming / de-foaming may also be used with the films. These components aid in the removal of air, such as entrapped air, from the film-forming compositions. S uch entrapped air may lead to non-uniform films. S imethicone is one particularly useful anti-foaming and/or de-foaming agent. In the embodiments of present invention, however, other anti-foam and/or de-foaming agents may

1&\ also be used.

To enhance the transmucosal or transdermal absorption of the thin films, various penetration enhancers may be used like Polysorbates, G lycols, Dimethyl sulfoxide, Azone, Pyrollidones, Terpenes, Terpenoids, Fatty acids, E sters of fatty acids, C hitosans, Cyclodextrins, etc.

Additionally, other pharmaceutically acceptable excipients known to those skilled in the art can also be used in oral dispersible film formulation. The objective of this invention was to achieve oral or transmucosal thin films that would comply/satisfy following standards:

P hysical appearance: Thin, translucent, non curving, non-tacky, flexible film with folding endurance of 25 or more. Dissolution: Not less than 75% in 45 minutes

Individual impurity: Not more than 1 %

Total impurity: Not more than 2%

Taste: Not less than acceptable_, on a scale of E xcellent (5), P leasant (4), ¾ Acceptable (3), Bitter (2) and Extremely bitter (1 ).

The examples given below in are illustrative embodiments of the invention and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All suchft, modifications and variations are intended to be included within the scope of the invention.

EXAMP L E S ¾ The tests for the quality are carried out as follows:

Methods of quality testing:

Diss olution: T he dissolution of levocetirizine thin films were carried out in 900 mL, P hosphate Buffer, pH 6.8 at 50 R P M at 37.0 eC e 0.5 eC temperature using US P dissolution Type 2 (Paddle) apparatus up to 30 minutes.

Folding endurance: Folding endurance was determined by repeated folding of the strip at the same place till the strip breaks. The number of times the strip is folded without breaking was computed as the folding endurance value.

Taste evaluation: T he compositions specified in the examples of this patent application were evaluated for the taste among a panel of 10 volunteers. Where score 1 meant extremely bitter and score 5 meant excellent

Taste Evaluation C riteria

Analysis of Impurities :

HPLC Method

Chromatographic conditions and Mobile phase:

Chromatographic Condition:

¾ 5 Column: Packing C18 - 250 mm X4.6 mm, 5 ι m (Princeton SPHER100 is suitable)

5Wave length: 230 nm

6 Flow Rate: 1.0 ml/min

6Injection Volume: 20 ι L

ft, 6Column Temperature: 30eC

Mobile Phase:

0.05 M Potassium dihydrogen phosphate and Acetonitrile, in the ratio of (60:40) was prepared and filtered. pH was adjusted to 6.0 e 0.05 with 10%of sodium¾ hydroxide.

Example 1

Formulation of Levocetirizine films

*P urified water gets evaporated during manufacturing process. P rocedure:

1. Weighed quantity of S ucralose and sunset yellow color was added to purified water and stirred for 10 min.

2. Weighed quantity of Levocetirizine dihydrochloridewas added to the ¾ solution prepared in step 1 and stirred for 10 min with the help of mechanical stirrer.

3. To the solution prepared in step 2, propylene glycol, glycerin, P olysorbate 80 were added and stirred for 1 5 min.

4. Then sucralose and Hydroxypropylmethyl cellulose were added and ft, stirred for 30 min.

5. In the last step Mentha oil was added and dispersion was stirred for 1 5 min.

6. The dispersion was casted on a support in uniform thickness and dried at a temperature of 80 eC .

¾ 7. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and 75% humidity.

8. The prepared films were evaluated for taste by the panel of volunteers.

9. The samples were analysed for physical appearance, dissolution and &\ impurities.

R esults:

Observation: T hin films with good physical properties were obtained having acceptable rate of dissolution; however, the levels of individual impurities arising due to chemical degradation and total impurities were unacceptable and the taste was also bitter. S ince the Example 1 represents prior art methods of making ¾ Levocetirizine films, a need was evident of achieving improvement in the method of making these films to achieve the objective of stipulated standard of quality.

Example 2

Formulation of Levocetirizine films using Polacrilin P otassium (Divinylbenzeneft, potassium methacrylate polymer) and Tocopherol acetate

*P urified water gets evaporated during manufacturing process. P rocedure:

2. Weighed quantity of Levocetirizine dihydrochloride and polacrilin potassium were added to the solution prepared in step 1 and stirred for 10 min with the help of mechanical stirrer. 3. To the solution prepared in step 2, propylene glycol, glycerin, P olysorbate 80 and Tocopherol acetate were added and stirred for 1 5 min.

4. Then sucralose and Hydroxypropylmethyl cellulose were added and stirred for 30 min.

¾ 5. In the last step Mentha oil was added and dispersion was stirred for 1 5 min.

7. The dried films were cut into suitable size, packed in triple layerft, aluminium pack and stored in stability chambers at 40°C temperature and

75% humidity.

8. The prepared films were evaluated for taste by the panel of volunteers.

9. The samples were analysed for physical appearance, dissolution and impurities at O, 15 days and 30 days.

¾ R esults:

Observation: Thin films with acceptable physical properties and dissolution were obtained and taste was also pleasant, but the chemical degradation was out of acceptable limit after 30 days period of storage.

Example 3

Formulation of Levocetirizine F ilms with polacrilin potassium, Tocopherol acetate and sodium hydroxide at drying temperature of 80°C . Name of Ingredients Qty in %

Levocetirizinedihydrochloride 8.33

S odium hydroxide 2.5

P olacrilin P otassium 6.25

Hydroxypropylmethyl C ellulose (low

47.88

viscosity grade)

P ropylene glycol 1 1.67

G lycerin 6.67

P olysorbate 80 6.67

S ucralose 3.33

Mentha oil 1 .67

S unset yellow color 0.03

Tocopherol acetate 5

P urified water Q.S .

*P urified water gets evaporated during manufacturing process.

P rocedure:

¾ 1. Weighed quantity of S ucralose and sunset yellow color was added to purified water and stirred for 10 min.

2. Weighed quantity of Levocetirizine dihydrochloride, polacrilin potassium and sodium hydroxide were added to the solution prepared in step 1 and stirred for 10 min with the help of mechanical stirrer.

ft, 3. To the solution prepared in step 2, propylene glycol, glycerin, P olysorbate

80 and Tocopherol acetate were added and stirred for 1 5 min.

5. In the last step Mentha oil was added and dispersion was stirred for 1 5¾ min.

6. The dispersion was casted on a support in uniform thickness and driedat a temperature of 80 eC . 7. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and 75% humidity.

8. The prepared films were evaluated for taste by the panel of volunteers. 9. The samples were analysed for physical appearance, dissolution and impurities at O, 15 days and 30 days.

Example 4:

Formulation of Levocetirizine F ilms with polacrilin potassium, Tocopherol acetate and sodium hydroxide at drying temperature of 50°C .

G lycerin 6.67

P olysorbate 80 6.67

S ucralose 3.33

Mentha oil 1.67

S unset yellow color 0.03

Tocopherol acetate 5

P urified water Q.S .

*P urified water gets evaporated c uring manufacturing process.

P rocedure:

1. The casting dispersion was prepared and casted on a support as ¾ described in the Example No. 3.

2. The casted dispersion was dried at a temperature of 50 eC .

3. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and 75% humidity.

ft, 4. The prepared films were evaluated for taste by the panel of volunteers.

5. The samples were analysed for physical appearance, dissolution and impurities at O, 15 days 1 , 2, 3, 4.5 and 6 months

¾ Observation: F ilms with desired characteristics were obtained. Example 5

Formulation of Levocetirizine F ilms with polacrilin potassium, Tocopherol acetate and sodium carbonate at drying temperature of 50°C .

*P urified water gets evaporated during manufacturing process

P rocedure:

1. The films were prepared using the procedure as described in Example 4ft, by replacing sodium hydroxide with sodium carbonate.

2. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and 75% humidity.

3. The prepared films were evaluated for taste by the panel of volunteers.¾ 4. The samples were analysed for physical appearance, dissolution and impurities at O, 15 days and 30 days. R esults

Example 6

Formulation of Levocetirizine F ilms with polacrilin potassium, Tocopherol acetate and sodium Bicarbonate at drying temperature of 50°C .

P rocedure:

1. The films were prepared using the procedure as described in Example 4 by replacing sodium hydroxide with sodium Bicarbonate.

2. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and

75% humidity.

3. The prepared films were evaluated for taste by the panel of volunteers.

4. The samples were analysed for physical appearance, dissolution and impurities.

R es ults :

Observation: T hin films with acceptable physical properties, dissolution and taste were obtained but the chemical degradation was out of acceptable limit

Example 7

Formulation of Levocetirizine F ilms with polacrilin potassium, Tocopherol acetate and P otassium Hydroxide at drying temperature of 50°C .

P ropylene glycol 1 1.67

G lycerin 6.67

P olysorbate 80 6.67

S ucralose 3.33

Mentha oil 1 .67

Tocopherol acetate 5

S unset yellow color 0.03

P urified water* Q.S .

P rocedure:

¾ 2. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and 75% humidity.

3. The prepared films were evaluated for taste by the panel of volunteers.

4. The samples were analysed for physical appearance, dissolution andft, impurities.

R es ults :

¾ Observation: Thin films with acceptable physical properties, dissolution and taste were obtained but the chemical degradation was out of acceptable limit Example 8

Formulation of Levocetirizine F ilms with polacrilin potassium, Tocopherol acetate and S odium Bicarbonate and Potassium Hydroxide at drying temperature of 50°C .

P rocedure:

1. The films were prepared using the procedure as described in Example 4 by replacing sodium hydroxide with sodium Bicarbonate and Potassiumft, hydroxide.

3. The prepared films were evaluated for taste by the panel of volunteers.¾ 4. The samples were analysed for physical appearance, dissolution and impurities. Results:

Observation: Thin films with acceptable physical properties, dissolution and taste were obtained but the chemical degradation was out of acceptable limit

Example 9

Formulation of Cetirizine hydrochloride films with Polacrilin Potassium, Tocopherol acetate and sodium hydroxide at drying temperature of 50 eC.

Name of Ingredients Quantity in %

Cetirizine hydrochloride 8.33

Sodium hydroxide 2.5

Polacrilin Potassium 6.25

Hydroxypropylmethyl cellulose

48

(Low viscosity polymer)

Propylene glycol 11.67

Glycerin 6.67

Polysorbate 80 6.67

S ucralose 3.33

Mentha oil 1.67

S unset yellow color 0.03

Tocopherol acetate 5

Purified water Q.S. P rocedure:

1. The casting dispersion was prepared and casted on a support as described in the Example No. 3.

2. The casted dispersion was dried at a temperature of 50 eC .

¾ 3. The dried films were cut into suitable size, packed in triple layer aluminium pack and stored in stability chambers at 40°C temperature and 75% humidity.

4. The prepared films were evaluated for taste by the panel of volunteers.

5. The samples were analysed for physical appearance, dissolution andft, impurities at O, 15 days 1 , 2, 3, 4.5 and 6 months.

Observation: F ilms with desired characteristics were obta

Claims

C laims :

A stable oral dispersible thin film comprising a 4-Diphenylmethyl-1 - piperazinyl derivative or its pharmaceutically acceptable salts.

The stable oral dispersible thin film; wherein the stability is characterized by:

(a) during storage of the film, level of the individua l impurities arising out of degradation of the 4-Diphenylmethyl-1 -piperazinyl derivative or its pharmaceutically acceptable salts does not exceed 1 % of the added drug,

(b) total impurities does not exceed 2% of the added 4- Diphenylmethyl-1 -piperazinyl derivative or its pharmaceutically acceptable salts; and

(c) the taste is not less than acceptable_, when scored by a taste panel on a scale of Excellent (5), P leasant (4), Acceptable (3), Bitter (2) and Extremely bitter (1 ).

3. The stable oral dispersible thin film according to claim 1 ; wherein the film is thin, translucent, non-curving, non-tacky and flexible with folding endurance of 25 or more, dissolution not less than 75% in 45 minute, &\ individual impurity not more than 1 % and total impurity not more than 2%

4. The stable oral dispersible thin film according to claim 1 further comprising one or more of (i) one more water soluble film-forming polymer/s, (ii) one or more water-insoluble film forming polymers, (iii) one or more stabilizer/s, (iv) one or more plasticizer/s, (v) one or more flavouring agents, (vi) one or more sweetening agent s, (vii) one or more taste masking agents, (viii) optionally surfactant/s, and other optional one or more pharmaceutically acceptable excipients or mixtures thereof.

The stable oral dispersible thin film according to claim 1 wherein the 4- Diphenylmethyl-1 -piperazinyl derivative or its pha rmaceutically acceptable salts comprises Buclizine, cyclizine, Meclizine, Oxatomide, Hydroxizine, C etirizine and levocetirizine.

The stable oral dispersible thin film according to claim 4 wherein:

(a) the water soluble film forming polymer is one or more selected from the group consisting of cellulose derivatives containing hydrophilic groups, such as cellulose, cellulose derivatives, cellulose ethers likehydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose (Na-C MC), starch and derivatives thereof e.g., maltodextrins, pullulan, gelatin, G ums like, gum acacia, gum arabic, tragacanth, guar, xanthangumetc, pectin, chitosan, chitosan derivatives, dextran, carrageenan, hyaluronic acid), polyalkylene oxides, polyalkylene glycols, polyethylene glycol (P E G ), polyvinyl pyrrolidone (PV P), polyvinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyacrylic acid, divinyl ether-maleic anhydride, polyphosphazene, polyphosphates, polyphosphonates, poly(2-alkyl-2-oxazolines), N-(2-hydroxypropyl) methacrylamide, and polyacrylamide, or combination thereof,

(b) the water-insoluble film forming polymer is one or more selected from the group consisting of ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, acrylic polymers, polyvinyl acetate, sodium sulphonated polyesters, carboxylated acrylics and shellac or combinations thereof,

(c) the stabilizer is one or more selected from the group consisting of one or more of an anti-oxidant s, a pH modifier/s, a chelating agent s, a preservative/s, a buffering agent or combination thereof,

(d) the plasticizer is one or more selected from the group consisting of glycerin, glycerol oleate, medium chain fatty acid, polyethylene glycol, propylene glycol, propylene glycol monocaprylate, propylene glycol dicaprylate, saccharide, sugar alcohols and triacetin,

(e) the flavouring agent is one or more selected from the group consisting of Menthol, cherry menthol, orange flavor, natural raspberry, spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds, Lemon flavor, grape flavor, lime flavor, vanilla flavor, chocolate flavor, clove flavor, peppermint flavor, apple flavor, pear flavor, pineapple flavor, peach flavor, apricot flavor, strawberry flavor, butter scotch flavor, mix fruit flavor, raspberry flavor, cherry flavor, prune flavor, cinnamon flavor, nutmeg flavor, coffee flavor, orange flavor, mango flavor, orange booster, raspberry flavor, papaya flavor, banana flavor and milk powder flavor,

(f) the sweetening agent is one or more selected from the group consisting of a monosaccharides, a disaccharide, a dextrose derivative such as dextrin, a polysaccharide, partially hydrolyzed starch, corn syrup solids, C rystalline hydrate forming sugars, artificial high intensity sweeteners, dihydrochalcones, monellin, steviosides, glycyrrhizin, or combination thereof,

(g) the taste masking agent is one or more selected from the group consisting of cyclodextrins, maltodextrins, Polacrilin P otassium or another ion exchange resin having same bitter masking property, amino acids, simethicone, E udragit S 100, gelatin, monoaminoglycerrhizinate, gelatinized starch, liposomes, lecithins or lecithin-like substances and salts,,

(h) the surfactant is one or more selected from the group consisting of sodium lauryl sulfate, mono and diglycerides of fatty acids and polyoxyethylene sorbitol esters, such as polyoxyethylene (20) sorbitan monostearate (Polysorbate 60) and polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), sodium salt of the monsulfated monoglyceride of hydrogenated coconut oil fatty acids, cocamidopropylbetaine or combination thereof,

(i) the other optional pharmaceutical agents are one or more selected from the group consisting of coloring agent, saliva stimulating agent opacifier, anti-caking agent, anti-foaming agent, de-foaming agent penetration enhancers,

e stable oral dispersible thin film according to claim 6 wherein:

(a) The said anti-oxident is one or more selected from the group consisting of -Tocopherol (Vitamin E ), B HA (butylated hydroxyanisole), B HT (butylated hydroxytoluene), sesamol, lecithin, Ascorbic acid (Vitamin C), G lutathione, Lipoic acid, gallates, resveratrol, polyphenols (e.g. ubiquinone, or coenzyme Q10), polyene compounds (e.g. <f -Carotene), ethyl hydrocaffeate, nor-dihydroguaiaretic acid, gentisic acid ethanolamine or ¾ combination thereof,

(b) the said acrylic acid polymers are one or more selected from the group sonsisting of methacrylate copolymer, methyl methacrylate- diethylaminoethyl methacrylate copolymer,

(c) the said preservative/s is/are one or more selected from the group ft, consisting of parabens, derivatives of parabens, benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, sodium benzoate, sorbic acid, salts of sorbic acid, propionic acid, salts of propionic acid, acetic acid, salts of acetic acid, citric acid, or combination thereof,

¾ (d) the said buffering agent is one or more selected from the group borate buffers, tartarate buffers, lactate buffers, citrate buffers, phosphate buffers (e.g. potassium phosphate monobasic), citric acid/phosphate buffers, carbonate/carbonic acid buffers, succinate/succinic acid buffers, and tris( hydroxy methyl) &\ aminomethane /hydrochloric acid buffers or combination thereof,

(e) the said:

i. monosaccharide is selected one or more from a group consisting of glucose (dextrose), fructose (levulose) and galactose, xylose, ribose, mannose, invert sugar (a mixture of fructose and glucose derived from sucrose), corn syrup solids,

ii. the dextrin derivative is maltodextrin, iii. the disaccharide is one or more selected from the group ¾ consisting of sucrose, maltose, lactose, cellobiose or combination thereof,

iv. the polysaccharide is one or more selected from the group consisting of amylose and amylo pectin, partially hydrolyzed starch,

ft, v. the said crystalline hydrate forming sugar is one or more selected from the group consisting of isomalt trehalose, and raffmose,

vi. an artificial high intensity sweetener is one or more selected from the group consisting of aspartame, neotame, ¾ saccharine, Acesulfame-K and cyclamate.

(f) The said:

i. the said coloring agent is selected one or more from the group consisting of pigments, dyes, natural food colors permitted for food and drug applications,

&\ ii. the said saliva stimulating agent is one or more selected from the group consisting of phosphoric acid, adipic acid, succinic acid, citric acid, malic acid, tartaric acid, fumaric acid, lactic acid, acetic acid, sorbic acid, cinnamic acid or combination thereof, . In preferred embodiments, a saliva stimulant represents about 0% to about 10% based on the dry weight of all the components of the film. iii. the opacifier is one or more selected from the group consisting of titanium dioxide and its derivative or combination thereof,

iv. In embodiments of this invention, an anti-tacking agent may be added to the film formulation,

v. The anti-tacking agent is one or more selected from the group consisting of silicon dioxide (Aerosil), talc or combination thereof,

vi. an anti-foaming / de-foaming is one or more selected from the group consisting of S imethicone or another anti-foam and/or de-foaming agent,

vii. the penetration enhancer is one or more selected from the group consisting of Polysorbates, G lycols, Dimethyl sulfoxide, Azone, Pyrollidones, Terpenes, Terpenoids, Fatty acids, E sters of fatty acids and C hitosans, Cyclodextrins.

A process for making stable oral dispersible thin film comprising a 4- Diphenylmethyl-1 -piperazinyl derivative or physiologically acceptable salts thereof.

The process of claim 8 comprising following steps:

a. adding sodium hydroxide before the film casting is done in an amount appropriate for providing stability to the film,

b. selecting temperature range for drying step of the film appropriate for getting a stable film, c. adding plasticizer/s in amount appropriate for overcoming effects of chemicals adverse to the folding endurance of at least 25; the folding endurance is number of times the film can repeatedly folded at the same place till the film breaks.

10. T he process of claim 8 wherein the 4-Diphenylmethyl-1 -piperazinyl derivative or physiologically acceptable salts comprises Buclizine, cyclizine, Meclizine, Oxatomide, Hydroxizine, Cetirizine and levocetirizine.