WO2012053006A2

WO2012053006A2 - Improved oral fast dissolving films comprising combination of polymers and method of preparation thereof

Info

Publication number: WO2012053006A2
Application number: PCT/IN2011/000715
Authority: WO
Inventors: Rajesh Jain; Sarabjit Singh; Paramjit Singh; Mansi Saildesai
Original assignee: Panacea Biotec Ltd
Priority date: 2010-10-18
Filing date: 2011-10-17
Publication date: 2012-04-26
Also published as: WO2012053006A3; WO2012053006A8

Abstract

The invention relates to an oral film having reduced adherence to oral cavity comprising water-soluble polymer as an essential polymer base in combination with film former, wherein the ratio of water-soluble polymer to the film former is about 25: 1 to about 250: 1 that is suitable for delivering drugs from various pharmacological categories ranging from conventional small molecules to proteins or peptides. In particular the invention relates to oral films which are bioequivalent to conventional immediate release oral dosage forms and exhibiting one or more favorable properties such as fast dissolution time, improved drug loading, improved mechanical properties (burst strength, tensile strength, modules of elongation).

Description

IMPROVED ORAL FAST DISSOLVING FILMS COMPRISING COMBINATION OF POLYMERS AND METHOD OF PREPARATION THEREOF

FIELD OF THE INVENTION:

The invention is in the field of pharmaceutical science. The invention relates to an oral film having reduced adherence to oral cavity comprising water-soluble polymer as an essential polymer base in combination with film former, wherein the ratio of water- soluble polymer to the film former is about 25: 1 to about 250: 1 that is suitable for delivering drugs from various pharmacological categories ranging from conventional small molecules to proteins or peptides. In particular the invention relates to oral films which is bioequivalent to conventional immediate release oral dosage forms and exhibiting one or more favorable properties such as fast dissolution time, improved drug loading, improved mechanical properties (burst strength, tensile strength, modules of elongation). The invention more specifically relates to an improved oral film comprising water-soluble polymer as an essential polymer base in combination with pectin as a film former, wherein the ratio of water-soluble polymer to the pectin is about 250:1 to about 25:1, that is suitable for delivering an active substance as mentioned above.

BACKGROUND OF THE INVENTION:

Oral administration of active substances in the form of tablets or capsules is extensively applied in the pharmaceutical and nutritional supplements industry. Conventional oral dosage forms such as tablets and capsules are meant to be swallowed whole or chewed with sufficient amounts of liquid to deliver the medication into the gastro-intestinal tract which is generally regarded as inconvenient. Liquids syrups and suspensions are an alternative to solid dosage forms, however in these dosage forms dosing accuracy cannot be ensured. Tablets may be formulated so as to be quick dissolving (orally disintegrating tablets) such that when placed on tongue they disintegrate rapidly in the oral cavity. Generally quick dissolving tablets are formed using complex multi-step manufacturing processes, thus making it cumbersome to manufacture. Using films for administration of active substances has several advantages over conventional forms. Using film strips to deliver drugs enhances patient compliance since it eliminates the need for water and the necessity to swallow a bulky pill. Such films are highly portable and excellent for use on-the-go. Importantly oral films can achieve fast onset of action since the drugs that dissolve rapidly in the mouth can give the perception that the drug acts faster than a traditional pill swallowed in the traditional way.

Oral films, such as those found in Listerine PocketPacks™, are known in the art. Other examples of products including such films are Neo Citran® Thin Strips™ for cough (with 25 mg of diphenhydramine hydrochloride), Theraflu® Thin Strips™ (with 25 mg of diphenhydramine hydrochloride) and Gas-X® Thin Strips™ (with 62.5 mg of simethicone) useful for the relief of multiple gas symptoms. Traditionally oral films made from pullulan, are known and most of the currently existing products are based on pullulan as the filmogenic component. See, e.g. U.S. Patent Numbers 3784390; 4623394; 5411945; 5518902. Pullulan is an expensive component, and it is not readily available. Other materials have been used in place of pullulan, including modified starches, such as maltodextrin, and starch derivatives, as described, for example, in WO 2005039543 and EP 1417895A1, respectively. However, these prior art films are based on very hygroscopic film-forming materials and on expensive packaging, both in terms of materials and technologies.

PCT application number WO2009085692 discloses an improvement in water-soluble polysaccharide films, such as pullulan films, by inclusion of low concentration of carboxymethylcellulose (CMC) in the film. The films exhibit improved physical properties such as tear strength, and retain good water-solubility.

PCT application number WO2007030754 discloses rapidly dissolving films which incorporate an anti-tacking agent. Film compositions with higher weight percent of pectin and lower weight percent water-soluble cellulose ether like sodium carboxymethylcellulose and sodium benzoate as an anti-tacking agent have been disclosed. PCT application number WO2009052421 film compositions comprising an active ingredient and a coating on the said film layer to provide the delivery of the active ingredient at the required rate. Film compositions with higher weight percent of pectin and lower weight percent water-soluble cellulose ether like sodium carboxymethylcellulose have been disclosed.

Each of the films of the representative prior art patents, discussed briefly above have certain disadvantages as compared to the components of the films and methods of the present invention. These preceding methods often require specialized equipment, employ mixtures of several excipients, and may result in the degradation of active ingredients. Still others are limited in the range of sizes that may be produced, as well as in the active component loading as a percent of total material weight. Despite the wide existence of oral films in the prior art there is a still need for providing an economically feasible, improved ,stable oral film that is easy to make and that can accommodate drugs with varying properties like for example active ingredients that are water insoluble.

Surprisingly it has been found that use of water-soluble polymers with film former in a ratio is of about 250: 1 to about 25:1 would yield a film which is capable of withstanding to various stress conditions. In particular it has been surprisingly found that use of water-soluble polymers with pectin in a ratio is of about 250:1 to about 25:1, would yield a film which is capable of withstanding to various stress conditions. Ideally, such a film will be flexible and resistant to breakage, have an enhanced active load and dissolve quickly with little or no water.

SUMMARY OF THE INVENTION:

It is an object of the present invention to provide an improved oral film having reduced adherence to the buccal cavity comprising water-soluble polymer as an essential polymer base in combination with film former, wherein the ratio of water-soluble polymer to film former is about 250: 1 to about 25: 1, that which can accommodate drugs from various pharmacological categories and at the same time exhibiting one or more favorable properties such as fast disintegration time, fast dissolution time, improved drug loading and improved mechanical properties. Another object of the present invention to provide improved oral film having reduced adherence to the buccal cavity comprising water-soluble polymer as an essential polymer base in combination with pectin, wherein the ratio of water-soluble polymer to pectin is about 250: 1 to about 25: 1.

Another object of the present invention is to provide an improved oral film composition comprising therapeutically effective amount of active pharmaceutical ingredient wherein said film is bioequivalent to conventional immediate release oral formulations that comprises same amount of said active pharmaceutical ingredient.

Yet another object of the present invention is to provide an improved oral film composition comprising therapeutically effective amount of tadalafil or pharmaceutically acceptable salts thereof wherein said oral film is bioequivalent to conventional immediate release oral formulations comprising same amount of tadalafil or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide an improved oral film composition comprising therapeutically effective amount of ondansetron or pharmaceutically acceptable salts thereof wherein said oral film is bioequivalent to conventional immediate release oral formulation comprising said amount of ondansetron or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide an oral film comprising water- soluble polymer as an essential polymer base in combination with film forming polymer, wherein the water soluble polymer is present in an amount from about 10% to about 90% by weight of the composition and film forming polymer is present in an amount from about 0.1 % to 10% by weight of composition.

A further object of the present invention is to provide an oral film which exhibits an in- vitro release of at least 60% in 5 minutes and at least 75% in 15 minutes. Another object of the present invention is to provide an oral film exhibiting burst strength ranging from about 200 to about 2500 kg/mm. A further object of the present invention is to provide an oral film exhibiting a tensile strength ranging from about 100 kg/mm² to about 400 kg/mm².

In an aspect film preparation of the invention is characterized in that it is rapidly dissolved in the oral cavity and can be taken without water, as a dosage form substitutive for a tablet.

In another aspect the present invention may be practiced using a simple casting method, by moulding the polymeric solution on a simple Petri dish, or on a glass plate using a path wet film applicator or casting equipment (to obtain a more homogenous film thickness), or by more sophisticated extrusion machines, and by allowing it to dry at room temperature, or in an oven or in a ventilated oven, or in a vacuum chamber.

DETAILED DESCRIPTION OF THE INVENTION

The term 'pharmaceutically acceptable excipient' according to the present invention means, but not limited to, any inactive ingredient which is required for the formulation of oral film according to present invention. Particularly the excipient includes, but not limited to, lubricants, buffering agents, stabilizers, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring aids, fragrances, release modifiers, adjuvants, plasticizers, granulating agents, diluents, binders, disintegrating agents, humectants, buffers, absorbents, glidants, anti-foaming agents, adhesives, anti- adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, release agents, extenders, antiblocking agents, antitacking agents in amounts suitable for their intended purpose. The term "immediate release" or "conventional immediate release" when used in this document, refers to a dosage form that allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug. The term includes tablets, capsules, orally disintegrating/dispersing tablet (ODT), and other dosage forms such as liquid preparations, intended for immediate release of active ingredient upon oral administration. An "immediate release" dosage form as used herein preferably refers to a dosage form adapted to release at least 80% of an active pharmaceutical ingredient in 60 minutes or less when measured in a type II dissolution apparatus as described in the United States Pharmacopoeia.

An "orally dissolving or orally dispersible tablet" ("ODT") refers to an uncoated tablet intended to be placed in the mouth where it can disperse rapidly before being swallowed .An ODT disintegrates within three minutes when tested according to the disintegration testing as described in European Pharmacopoeia .

"About" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which the term is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

Cmax or peak plasma exposure as described herein refers to the point of maximum concentration of drug in plasma and is expressed in ng/ml. Area under curve (AUC) or total plasma exposure refers to the total integrated area under plasma level time profile and expresses the total amount of drug that comes into systemic circulation after administration and is expressed in ng.h/ml

The term "bioequivalent" means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.Two compositions can be considered as "bioequivalent" if the 90% Confidence Interval of the relative mean C_max and AUC of the test to reference is within 80.00% to 125.00%. The compositions of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well any of the additional or optional ingredients, components, or limitations described herein. All percentages, parts and ratios are based upon the total weight of the dry film composition of the present invention, unless otherwise specified. All such weights as they pertain to the listed ingredients are based on the dry weight of the composition, unless otherwise specified.

Disclosed herein is an improved oral fast dissolving films which comprising water- soluble polymer as an essential polymer base in combination with film former such as pectin, wherein the ratio of water-soluble polymer to film former is about 250:1 to about 25:1 and any optional additives, methods of making the film, and packages made from the film. In embodiments, the films can have one or more favorable properties such as improved mechanical properties, selected from one or more of fast disintegration time, fast dissolution time, increased tear strength, increased tensile strength, increased modulus of elongation, and decreased elongation at break, reduced adherence to the buccal cavity and maintains such integrity in normal conditions as well as in various stress conditions. The preferred films of the invention will have one or more improved mechanical properties while maintaining desirable disintegration and/or dissolution times.

The base polymer for the film is "water-soluble polymer" which means polymers that dissolve or disperse in water to give a colloidal solution or dispersion at a temperature of less than 30 degree C. (for example from 10 to 20.degree. C). Generally the water- soluble polymers will have a solubility in water of at least 20 mg/ml, suitably at least 30 mg/ml at a temperature of 10 to 20.degree.C (wherein the solubility is determined in un-buffered distilled water). Suitable water-soluble polymers include but not limited to, those listed in the Handbook of Pharmaceutical Excipients, 3.sup.rd Edition American Pharmaceutical Association, for example methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl ethylcellulose, a water-soluble salt of carboxymethylcellulose (for example sodium carboxymethylcellulose) and a water- soluble salt of carboxymethyl hydroxyethyl cellulose (for example sodium carboxymethyl hydroxyethylcellulose). More particularly suitable water-soluble polymer is selected from, for example, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and a water-soluble salt of carboxymethylcellulose (for example sodium carboxymethyl cellulose) pullulan, maltodextrin etc. In a preferred embodiment the water-soluble polymer is a water-soluble alkaline metal salt of carboxymethylcellulose, particularly sodium carboxymethylcellulose. Suitably the water-soluble alkaline metal salt of carboxymethylcellulose is one with an average degree of substitution of approximately 0.7 to 1.2, for example from 0.8 to 0.95 wherein here degree of substitution refers to the average number of carboxymethyl groups per anhydroglucose ring of the cellulose. Generally the water-soluble alkaline metal salt of carboxymethylcellulose is a low viscosity grade, suitably one with a dynamic viscosity of approximately 10 to 2500 cP, for example from 10 to 1500 cP, such as from 10-15 cP or from 900 to 1500 cP, wherein the viscosity is measured in a 1% w/v aqueous solution of the carboxymethylcellulose at 25.degree.C.

In another preferred embodiment the compositions of present invention comprise at least one water-soluble polymer which is hydroxypropylmethylcellulose (HP C) and optionally an additional water-soluble polymer such as maltodextrin. HPMC is available from Dow chemical company under the trademark METHOCEL. It is available in different grades depending upon viscosity and degree of substitution. HPMC E5 and HPMC El 5 are preferably used. HPMC E5 is hydroxypropylmethylcellulose having a nominal viscosity of 4-7 millipascal seconds (mPa.s). HPMC El 5 is hydroxypropylmethylcellulose having a nominal viscosity of 11-20 mPa.s.

In another preferred embodiment the compositions of present invention comprise at least one water-soluble polymer which is hydroxypropylmethylcellulose (HPMC) and optionally an additional water-soluble polymer such as maltodextin and a film forming agent such as pectin.

In another preferred embodiment the compositions of present invention comprise at least one water-soluble polymer which is pullulan and optionally an additional water- soluble polymer and a film forming agent such as pectin.

In another embodiment the water-soluble polymer is sodium carboxymethyl cellulose which may be of any suitable grade to yield a film having desired properties. Suitable grades of sodium carboxymethylcellulose are available from Hercules, Inc. of Wilmington Delaware, USA, for example under the trade name BLANOSE with three degree of substitutions (DS) as 7 (7H5SF, 7H4F, 7HOF, 7H3SF, 7HF, 7M31F, 7M8SF, 7MF, 7M1F, 7LF), 9 (9H4F, 9M65F, 9M31F) and 12 (12M31F) with different viscosity ranges as low, medium and high. Sodium carboxymethylcellulose is also available commercially under the trade name of Akucell, Walocel^™ CRT-A and Walocel^™ CRT, Walocel^™ C, Clear + stable^™, Avicel.The total compounding amount of the preferred water-soluble polymer is from 10 to 90% by weight, and preferably from 40 to 80% by weight in all.

The film-forming agent according to the present invention provides a physiologically acceptable film and can be selected from the group consisting of pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures thereof.

A preferred film former is Pectin which is available in USP grades and has few regulatory barriers around the world. Some competitive products such as gelatin, modified starch, and synthetic polymers have more regulatory barriers. The pectin film may be formed from many types of pectin including high methoxyl, low methoxyl, and low methyl ester amidated type pectins. Preferably, high methoxyl pectins are used. The galacturonic acid residues in pectin are partly esterified and present as the methyl ester. The degree of esterification is defined as the percentage of carboxyl groups esterified. Pectin with a degree of esterification ("DE") above 50% is named high methyl ester ("HM") pectin or high ester pectin and one with a DE lower than 50% is named low methyl ester ("LM") pectin or low ester pectin. Most pectin found in fruits and vegetables are HM pectins. One suitable HM pectin is D Slow Set (available from CP Kelco ApS).The total compounding amount of the preferred film former (pectin) is from 0.1 to 10% by weight, and preferably from 0.1 to 5% by weight in all.

Other optional film additives are known in the art, especially for polysaccharide films, for providing various functionalities. The film composition and film can thus contain auxiliary film agents and processing agents, such as, but not limited to, lubricants, buffering agents, stabilizers, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring aids, fragrances, release modifiers, adjuvants, plasticizers, granulating agents, diluents, binders, disintegrating agents, humectants, buffers, absorbents, glidants, anti-foaming agents, adhesives, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, release agents, extenders, antiblocking agents, antitacking agents, antifoams and other functional ingredients, in amounts suitable for their intended purpose. The flavorings that can be used include those known to the skilled artisan, such as natural and artificial flavors. These flavorings may be chosen from synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof. Representative flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil.

Also useful are artificial, natural or synthetic flavors such as vanilla, chocolate, coffee, cocoa and fruit essences including apple, strawberry, raspberry, cherry, plum and so forth. These flavorings can be used individually or in admixture.

Plasticizers (also referred to as humectants in some contexts) are preferred for making a flexible film. Suitable plasticizers include sugar alcohols such as sorbitol, mannitol, maltitol, glycerol, and propylene glycol. As less plasticizer is used, the film becomes more brittle; whereas as more plasticizer is used the film loses tensile strength. The total compounding amount of the preferred plasticizer is from 1 to 50% by weight, and preferably from 1 to 15% by weight in all.

Emulsifiers are also preferred optional components. Preferred emulsifiers will have a hydrophile/lipophile balance (HLB) in a range of about 8 to 20, for example 15. The HLB scale is a numerical scale, extending from 0 to approximately 20, where lower numbers denote more lipophilic and hydrophobic substances, and higher numbers denote more hydrophilic and lipophobic substances. The affinity of a compound for water, or for oily substances, is determined and its HLB value is assigned experimentally. One of the preferred emulsifiers is polysorbate 80 or Tween 80.The total compounding amount of the preferred emulsifier is from 1 to 50% by weight, and preferably from 1 to 15% by weight in all. Anti-foaming and/or de-foaming components may also be used with the films of the present invention. These components aid in the removal of air, such as entrapped air, from the film-forming compositions. As described above, such entrapped air may lead to non-uniform films. Simethicone is one particularly useful anti-foaming and/or de- foaming agent. The total compounding amount of the preferred anti foaming agent is from 1 to 50% by weight, and preferably from 1 to 15% by weight in all.

Sweeteners useful in the practice of the present invention include both natural and artificial sweeteners. Suitable sweetener include water soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, glatose, fructose (levulose), sucrose (sugar), maltose, water soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts dipeptide based sweeteners, such a L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalaine methyl ester (aspartame) or other sweeteners such as Sucralose. The total compounding amount of the preferred sweetener is from 0.1 to 10% by weight, and preferably from 0.1 to 5% by weight in all. The film of the invention may include specific essential oils like menthol, thymol, methyl salicylate, eucalyptol and the like. Generally the amount is from about 1 to about 20 wt % of the film composition, preferably about 1 to about 10 wt %.

The compositions of the present invention can also contain coloring agents or colorants. The coloring agents are used in amounts effective to produce the desired color and include natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as FD&C dyes and lakes.

Saliva stimulating agents can also be added to the oral films according to the present invention. Saliva stimulating agents include food acids such as citric, lactic, malic, succinic, ascorbic, adipic, fumaric and tartaric acids. Preferred food acids are citric, malic and ascorbic acids. The oral films according to the invention may have one or more layers and typically have a thickness of from 5-3000 - preferably 10-1000, more preferably 20-500 and in particular 30-300 - micrometers. In a preferred embodiment the film is monolayered. One aspect of the invention provides an improved oral film composition in which all the ingredients are uniformly dispersed to form a single unit dosage form. The term 'film' or 'strip' can be interchangeably used for compositions of the present invention.

As used herein, the terms "active," "active agent," and "active ingredient" are used interchangeably and are meant to refer to a substance intended to be delivered, the substance being capable of imparting a desired action or effect. Such substances include, but are not limited to, pharmaceuticals, medicaments, drugs, therapeutic agents, diagnostic agents, cosmetic agents, nutritional supplements and mixtures thereof. The terms "active," "active agent," and "active ingredient" include unmodified forms or separately processed forms of the active (such as encapsulated or granulated forms). The encapsulated and/or granulated forms are generally used to provide special delivery characteristics prior to film preparation.

There is no particular limitation on the drugs used in the invention, as long as they can be orally administered. Examples of useful drugs include anti-emetics, anti-nauseants cardiovascular agents such as, antianginal drugs, anti-arrhythmics, anti-coagulants, anti-thrombotic drugs, coronary dilators, anti-hypertensive drugs, central nervous system stimulants, dopamine receptor agonists anti-anxiety agents cholinesterase inhibitors, anesthetics, anti-convulsants, hypnotics, anti-depressants, anti-parkinsonian agents psychotherapeutic agents,anti-diabetic agents, anti-cholesterolemics, premature ejaculation management agents , drugs used to treat erectile dysfunction parasympatholytics, parasympathomimetics, motion sickness management agents,anti- diarrhea preparations, antidotes, anti-histamines, anti-inflammatory agents, anti-lipid agents, analgesics, , anti-asthmatics, anti-stroke agents, anti-thyroid preparations, antitumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti- tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non- systemic anti-infective agents, anti-neoplastics, , anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, , contraceptives, decongestants, dietary supplements, , endometriosis management agents, enzymes, fertility agents, gastrointestinal agents,hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations,muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, prostaglandins, , respiratory agents, sedatives, smoking cessation aids such as bromocryptine and nicotine, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, , anti-ulcer agents, anti-inflammatory substances, , cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, neuromuscular drugs, hyper-and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, ariti-spasmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, cough suppressants, mucolytics, DNA and genetic modifying drugs, proteins ,peptides and combinations thereof.

Non-limiting examples of active pharmaceutical agents used according to the present invention are dapoxetine,donepezil hydrochloride; ondansetron; desloratadine; olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil; tadalafil;yohimbine galantamine; diclofenac potassium; buprenorphine HC1; naloxone HC1 dehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizine hydrochloride; loratadine; ambroxol hydrochloride; apomo hine; ascorbic acid; betamethasone; caffeine; dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane; piroxicam and combinations thereof.

In a preferred embodiment of the present invention, the active drug may comprise one or more anti-emetics. Such anti-emetics include and may be selected from one or more of the group consisting of: ondansetron, granisetron, palonosetron, dronabinol, aprepitant, ramosetron, metopimazine, nabilone, tropisetron, metoclopramide, prochlorperazine, trimethobenzamide, dimenhydrinate, prochlorperazine and dolasetron.

A particularly preferred pharmaceutically active agent for use in this invention is ondansetron, preferably as its base. Ondansetron is chemically known as (±) 1,2,3,9 tetrahydro-9-methyl-3-[(2-methyl-lH- imidazol-l-yl) methyl] -4H-carbazol-4-one and its base is represented by the following chemical structure:

The film most preferably contains 4 to about 8 mg of ondansetron base and is preferably formulated according to the general formulation techniques described herein. The invention provides an improved oral film for the treatment or prevention of emesis, including emesis resulting from postoperative nausea and vomiting, chemotherapy induced nausea and vomiting, and radiation induced nausea and vomiting.

In an embodiment oral film comprises 2%-85% ondansetron; 0.05-10% of film forming polymer; 20-90% of water soluble polymer and optionally other pharmaceutically acceptable excipients

In a preferred embodiment oral film comprises about 5-25% of ondansetron; 0.1-2% of pectin and about 10-50% hydroxypropylmethyl cellulose; 10-50% of maltodextrin and optionally other pharmaceutically acceptable excipients.

Preferred embodiments include oral films prepared according to the present invention incorporating drugs for treatment of erectile dysfunction. Erectile dysfunction therapies include, but are not limited to, drugs for facilitating blood flow to the penis, and for effecting autonomic nervous activities, such as increasing parasympathetic (cholinergic) and decreasing sympathetic (adrenersic) activities. Useful non-limiting drugs include sildenafil, (Viagra®), tadalafil (Cialis®), vardenafil, apomorphines (Uprima®), yohimbine hydrochloride (Aphrodyne®), alprostadil (Caverject®) and the like.

In a particularly preferred embodiment the pharmaceutically active agent is Tadalafil. Tadalafil is chemically known as Pyrazino[ ,2': l,6]pyrido[3,4-b]indole-l,4-dione, 6- (1,3- benzodioxol-5-yl)- 2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-, (6R, 12aR) is represented by the following chemical structure:

The film most preferably contains 10 to about 20 mg of tadalafil and is preferably formulated according to the general formulation techniques described herein. The invention provides an improved oral film for the treatment of erectile dysfunction.

In an embodiment the oral film comprises 2-85% tadalafil, 0.05%- 10% of film forming polymer, 15% -90% of water soluble polymer and optionally other pharmaceutically acceptable excipients.

In a preferred embodiment the oral film comprises 15-50% tadalafil; 0.2-2% pectin; 15- 60% of hydroxypropylmethyl cellulose and optionally other pharmaceutically acceptable excipients. It has been surprisingly found oral films comprising therapeutically effective amount of ondansetron/tadalafil according to the present invention are bioequivalent to conventional immediate release dosage forms comprising same amount of ondansetron/tadalafil.

The films of the present invention may be mucoadhesive, whose advantage resides in their ability to bypass the gastrointestinal tract, and barriers in the gastrointestinal tract to drug absorption such as first pass metabolism and decomposition of the active ingredient in the stomach.

Alternatively the films of the present invention may be non-mucoadhesive which mimics the pharmacokinetic profile conventional immediate release solid oral dosage forms and are bioequivalent to and interchangeable with existing orally administered drug products. The films of the present invention must be formed into a sheet or film prior to drying. After the desired components are combined to form a multi-component matrix, including the polymer, water, and active or other components as desired, the combination is formed into a sheet or film, by any method known in the art such as extrusion, coating, spreading, casting or drawing the multi-component matrix.

Casting or coating methods are particularly useful for the purpose of forming the films of the present invention. For example, once a suspension containing the active agent(s) and water-soluble polymer(s) is prepared, as will be described in greater detail below, the suspension may be cast onto a substrate, such as polyester, using knife, bar, or extrusion die coating methods, and dried to form a film.

Alternatively coating methods may also be employed. Examples include reverse roll coating, gravure coating, and immersion or dip coating, metering rod or Meyer bar coating, slot die or extrusion coating, gap or knife over roll coating, air knife coating, curtain coating, or combinations thereof.

The oral film composition may be dried by a process not limited to drying oven, drying tunnel, vacuum drier, or other such drying equipment.

Films according to the invention may be desirably packaged in sealed, air and moisture resistant packages to protect the active from exposure to oxidation, hydrolysis, volatilization and interaction with the environment. The packaging should ensure that the volatile active substances and/or aromatic substances contained in the film are maintained until the time of consumption and there is no permeation of vapour and gases. Further the packaging should also ensure that it is resistant to water and air contamination, provides a prolonged shelf life to the pharmaceutical or cosmetic active ingredient, reduce contamination, promote ease of access to the contents of the package, and reduce the ease of access to the contents through child tampering.

Packaging materials comprising of paper, cardboard, plastic films (for example, polyethylene, polyethyleneterephthalate, polypropylene, polystyrene, cellophane, polyamides, polycarbonates, ethylene vinylacetate copolymer), and metal foils (for example, aluminum foil) may be considered. The invention is described in detail with reference to the following examples, but the present invention is not deemed to be limited thereto.

EXAMPLES

Examples 1 - 2

wt. in mg/strip

Ingredients Ex.1 Ex.2

Ondansetron 8.0 8.0

Pectin 0.1 0.2

Sodium CMC 23.0 15.7

Glycerol 4.6 4.7

Tween 80 4.6 6.2

Simethicone 4.6 6.2

Sucralose 0.3 0.5

Menthol 1.7 2.4

Methyl salicylate 0.2 0.3

Distilled water 3.7 7.0

Process

Step I: Ondansetron (base) was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and Tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose and optionally methyl salicylate were added and dissolved. Sodium CMC was the added and hydrated.

Step II: Pectin solution was prepared by dissolving pectin in distilled water using a waterbath.

Step III: The solution prepared in step II was added to step I and mixed.

Step IV: Menthol was added to the solution from step III and dissolved. The solution prepared in step IV was cooled and films were casted. The films were dried and packed.

Examples 3 - 4

wt. in mg/strip

Ingredients Ex.3 Ex.4

Ondansetron 8.0 4.0

Pectin 0.5 0.5 Maltodextrin 15.3 16.8

HPMC E15 15.3 16.8

Glycerol 3.0 3.4

Tween 80 3.0 3.4

Simethicone 1.4 3.4

Locust bean gum 0.15 0.2

Carrageenan 0.15 0.2

Sucralose 0.3 0.3

Menthol 1.2 1.3

Distilled water 3.8 4.5

Process

Step I: Ondansetron was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and Tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose was added and dissolved.

Step III: HPMC, Maltodextrin, Locust bean gum and carrageenan was added to the solution prepared in step II and the solution was stirred for 1.0 hr thereby allowed the polymers to hydrate.

Step IV: The solution prepared in step III was added to step I and mixed.

Step V: Menthol was added to the solution from step IV and dissolved.The solution prepared in step V was cooled and films were casted.The films were dried and packed. Example 5

Ingredients wt. in mg/strip

Ondansetron 4.0

Pectin 0.6

Pullulan 35.5

D-sorbitol 3.7

Glycerol 3.7

Tween 80 1.9

Simethicone 1.7 Locust bean gum 0.2

Carrageenan 0.2

Sucralose 0.4

Menthol 1.2

Distilled water 3.4

Process

Step I: Ondansetron was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and Tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose and D - sorbitol were added and dissolved.

Step III: Pullulan, Locust bean gum and carrageenan was added to the solution prepared in step II and the solution was stirred for 1.0 hr thereby allowed the polymers to hydrate.

Step IV: The solution prepared in step III was added to step I and mixed.

Step V: Menthol was added to the solution from step IV and dissolved. The solution prepared in step V was cooled and films were casted. The films were dried and packed.

Example 6

Ingredients wt. in mg/strip

Tadalafil 20.0

Pectin 0.1

Sodium CMC 21.4

Glycerol 4.3

Tween 80 4.3

Simethicone 4.3

Sucralose 0.3

Menthol 1.6

Methyl salicylate 0.2

Distilled water 5.1

Process Step I: Tadalafil was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and Tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose and optionally methyl salicylate were added and dissolved. Sodium CMC was the added and hydrated.

Step II:Pectin solution was prepared by dissolving pectin in distilled water using a waterbath.

Step III: The solution prepared in step II was added to step I and mixed.

Example 7

Ingredients wt. in mg/strip

Tadalafil ^'. 20

Pectin 0.5

Maltodextrin 16.4

HPMC El 5 16.4

Glycerol 3.3

Tween 80 3.3

Simethicone 3.3

Locust bean gum 0.2

Carrageenan 0.2

Sucralose 0.3

Menthol 1.0

Distilled water 4.0

Process

Step I: Tadalafil was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and Tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose was added and dissolved.

Step II: Pectin solution was prepared by dissolving pectin in distilled water using a waterbath. Step III: HPMC, Maltodextrin, Locust bean gum and carrageenan was added to the solution prepared in step II and the solution was stirred for 1.0 hr thereby allowed the polymers to hydrate.

Step IV: The solution prepared in step III was added to step I and mixed.

Step V: Menthol was added to the solution from step IV and dissolved.The solution prepared in step V was cooled and films were casted. The films were dried and packed.

Example 8

Ingredients wt. in mg/strip

Tadalafil 20.0

Pecti 0.5

Pullulan 25.8

D-sorbitol 3.4

Glycerol 3.4

Tween 80 1.7

Simethicone 1.5

Locust bean gum 0.2

Carrageenan 0.2

Sucralose 0.3

Menthol 1.0

Distilled water 4.2

Process

Step I: Tadalafil was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and Tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose and D - sorbitol were added and dissolved.

Step III: Pullulan, Locust bean gum and carrageenan was added to the solution prepared in step II and the solution was stirred for 1.0 hr thereby allowed the polymers to hydrate. i

Step IV: The solution prepared in step III was added to step I and mixed. Step V: Menthol was added to the solution from step IV and dissolved.The solution prepared in step V was cooled and films were casted. The films were dried and packed Examples 9-11

wt in mg/strip

Ingredients Ex. 9 Ex.10 Ex. 11

Tadalafil 20.0 20.0 20

Pectin 0.5 0.5 1.6

HPMC El 5 17.7 17.5 21.4

HPMC E3 12.4 12.3 20.2

Glycerol 3.5 5.3 3.3

Tween 80 1.8 - 3.3

Simethicone 1.8 0.9 3.3

Xanthan gum 0.2 - -

Sucralose 0.4 0.4 0.4

Menthol 0.9 - 0.9

Distilled water 3.0 3.2 3.9

Process

Step I: Tadalafil was added to glycerol and dispersed. Distilled water was then added to form a homogeneous solution. Simethicone and optionally tween 80 then added to the prepared homogeneous solution and dissolved. Sucralose was added and dissolved.

Step III: HPMC El 5, HPMC E3 and optionally xanthan gum was added to the solution prepared in step II and the solution was stirred for 1.0 hr thereby allowed the polymers to hydrate.

Step IV: The solution prepared in step III was added to step I and mixed.

Step V: Menthol was optionally added to the solution from step IV and dissolved. The solution prepared in step V was cooled and films were casted. The films were dried and packed.

Example 12

Table 1 : Amount of Ondansetron released from the dosage form as a function of time.

Time interval (mins) Mean % Drug released 3.0 78

6.0 95

9.0 99

The amount of drug released from the oral film as exemplified in Example 4 is determined by paddle method (Apparatus USP type II: paddle with sinkers ) by immersing the oral film in dissolution vessel with sinkers that contains 500ml of 0.1 N HC1 , at a speed of 50 rpm Aliquots of the medium are withdrawn at various time points. The aliquots are then analyzed to determine the concentration of dissolved active ingredient using standard methodology. The dissolution test determines that 99% ondansetron was dissolved within 9 minutes.

Example 13

Table 2: Amount of Tadalafil released from the dosage form as a function of time.

Time interval (mins) Mean % Drug released

3.0 70

6.0 89

9.0 94

The amount of drug released from the oral film as exemplified in Example 9 is determined by paddle method (Apparatus USP type II: paddle with sinkers) by immersing the oral film in dissolution vessel with sinkers that contains 1000ml of 0.5% Sodium lauryl sulfate SLS in distilled water at a speed of 50 rpm .Aliquots of the medium are withdrawn at various time points. The aliquots are then analyzed determine the concentration of dissolved active ingredient using standard methodology. The dissolution test determines that 94% tadalafil was dissolved within 9 minutes.

Example 14

Table 3: Measurement of burst strength (breaking strength) for Ondansetron Oral Film

Sr.No Film thickness Distance travelled by Time Force applied Burst str

(mm) weight (mm) (sec) (kg) (kg/m

1 0.0620 3.118 1.560 1.244 2006,

2 0.0615 3.728 1.865 1.209 1965. 3 0.0610 2.118 1.060 0.790 1295.1

4 0.0625 2.378 1.190 0.842 1347.:

Mean 1653.64

Table 4: Measurement of burst strength (breaking strength) for Tadalafil oral film

Sr. No. Film thickness Distance travelled by Time (sec) Force applied Burst

(mm) weight (mm) (kg) strengtl

(kg/mm

1. 0.0810 0.969 0.485 0.2914 359.75

2. 0.0815 1.039 0.520 0.3571 438.16

3. 0.0822 1.069 0.535 0.3531 429.56

4. 0.0806 1.039 0.520 0.3241 402.11

Mean 407.40

Equipment used : TA.XT2 texture analyzer equipped with 5 kg load cell

(manufactured by stable Micro Systems, UK).

Method : Compression

Speed : 2 mm/sec

Distance : 5 mm

Burst strength is the maximum stress required to puncture the film sample. It is calculated by the formula: Burst strength = Load at failure ^χ 100/ Film thickness

Burst strength of ondansetron oral films as exemplified by example 4 and tadalafil oral films as exemplified by example 9 is illustrated in Tables 3 and 4.The average value from four tests was determined and was taken as the burst strength (breaking strength).

Example 15

Table 5: Measurement of tensile strength and percent elongation of Ondansetron oral films

Sr. No Film Film Film Force Distance of Time Tensile

width length thickness applied stretched (sec) strength Elori

(mm) (mm) (mm) (kg) film (mm) (kg/ mm )

1. 20.0 30.0 0.0610 2.5352 - 0.519 0.260 207.80 1 2. 20.0 30.0 0.0625 2.5867 - 0.559 0.280 206.93 1

3. 20.0 30.0 0.0613 2.6898 - 0.469 0.235 219.40 1

4. 20.0 30.0 0.0605 2.6411 - 0.519 0.260 218.27 1

Mean 213.10 1

Table 6: Measurement of tensile strength and percent elongation of Tadalafil oral films

Sr. Film Film Film Force Distance of Time Tensile %

No. width length thickness applied stretched (sec) strength Elongat

(mm) (mm) (mm) (kg) film (mm) (kg/ mm²)

1. 20.0 30.0 0.0802 2.7465 - 0.529 0.265 171.22 1.76

2. 20.0 30.0 0.0802 2.7672 - 0.409 0.205 172.52 1.36

3. 20.0 30.0 0.0803 2.5719 - 0.519 0.260 160.14 1.73

4. 20.0 30.0 0.0805 2.5415 - 0.619 0.310 157.86 2.06

Mean 165.44 1.73

Measurement of Tensile Strength:

Equipment used : TA.XT2 texture analyzer equipped with 5 kg load cell (Manufacture by Stable Micro Systems, UK).

Method : Tension

Speed : 2 mm/sec

Distance : 5 mm

Tensile strength is the maximum stress applied to a point at which the film specimen breaks. It is calculated by the formula:

Tensile strength = Load at failure x 100/ Film thickness x Film width

Percent elongation: When stress is applied, a film sample stretches and this is referred to as strain. Strain is the deformation of film divided by original dimension of the sample. It is calculated by the formula:

Percent Elongation (mm) = Increase in length of the film x 100/ Initial length of the film

Tensile strength and percent elongation of ondansetron oral films as exemplified by example 4 and tadalafil oral films as exemplified by example 9 is illustrated in Tables 5 and 6. The average value from four tests was determined and was taken as the tensile strength. Example 16

A bio-equivalence study was carried out with the objective to compare the rate and extent of absorption of Ondansetron Oral Strips (8.0 mg - two strips of 4 mg each) as exemplified in example 4 with Zofran® orally disintegrating tablet (Ondansetron 8 mg- as reference product) of Glaxo Smithkline, USA, in 38 healthy, adult, male, human subjects under fasting conditions. The venous blood samples were withdrawn at specific time intervals and plasma drug levels were monitored using a validated method and pharmacokinetic parameters Cmax, AUCo-t and AUCo-inf were evaluated.

Sr.no Parameters Ondansetron oral Zofran® 90% Confidence

strips Intervals

Lower Upper limit limit

1 Cmax (ng/ml) 59.578 54.141 101.0 120

2 AUC, (ng.h/ml) 358.353 320.540 101.0 124.0

3 AUC_inf(ng.h 372.666 333.281 100.0 125.0

/ml)

From the above data it is inferred that Ondansetron Oral Strips (8.0 mg - two strips of 4 mg each) as exemplified in Example 4 is bioequivalent to Zofran® orally disintegrating tablet.

Example 17

A bio-equivalence study was carried out with the objective to compare the rate and extent of absorption of Tadalafil Oral Strips (20 mg) as exemplified in Example 9 with Cialis® (20 mg Oral Tablet manufactured by Eli Lilly and Company USA -as a reference product), in 36 normal, healthy, adult, male, human subjects under fasting conditions. Test (T) refers to Tadalafil Oral Strips (20 mg) as exemplified in Example 9 and Reference(R) refers to Cialis® (20 mg Oral Tablet manufactured by Eli Lilly and Company USA

Parameters Ratio of least square means T/R (%) 90% Confidence Interva Lower limit Upper lir

Cmax (ng/ml) 115.0 108.0 122.0

AUC, (ng.h/ml) 110.0 105.0 117.0

AUCinf (ng.h /ml) 115.0 106.0 125.0

From the above data it is inferred that Tadalafil Oral Strips (20.0 mg - strip) as exemplified in Example 9 is bioequivalent to Cialis®. (20 mg Oral Tablet manufactured by Eli Lilly and Company USA)

Claims

1. An oral fast dispersing or dissolving film for delivery of active comprising therapeutically effective amount of an active pharmaceutical agent, atleast one water soluble polymer as essential polymer base in combination with film forming polymer in a ratio of about 25: 1 to about 250: 1.

An oral film according to claim 1 wherein, the water soluble polymer is present in an amount from about 10% to about 90% by weight of the composition and film forming polymer is present in an amount from about 0.1% to 10% by weight of composition.

An oral film according to claim 1 wherein, the water soluble polymer is selected from the group consisting of methylcellulose, hydroxyalkylcelluloses, a water- soluble salt of carboxyalkylcelluloses, pullulan, maltodextrin.

An oral film according to claim 3 wherein, the hydroxyalkylcelluloses is hydroxypropylmethyl cellulose.

An oral film according to claim 1 wherein ,the film forming polymer is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, locust bean gum, carrageenan, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures thereof.

An oral film according to claim 1, having a thickness of about 5μ to about 3000μ.

7. An oral film according to claim 1, wherein the active pharmaceutical agent is selected from the group comprising anti-emetics, anti-nauseants, cardiovascular agents, antianginal drugs, anti-arrhythmic s, anti-coagulants, anti-thrombotic drugs, coronary dilators, anti-hypertensive drugs, drugs for treatment central nervous system disorders, dopamine receptor agonists anti-anxiety agents cholinesterase inhibitors, anesthetics, anti-convulsants, hypnotics, anti- depressants,anti-parkinsonian agents psychotherapeutic agents,anti-diabetic agents, anti-cholesterolemics, premature ejaculation management agents , drugs used to treat erectile dysfunction, parasympatholytics, parasympathomimetics, motion sickness management agents and combinations thereof.

An oral fast dispersing or dissolving film according to claim 1, comprising therapeutically effective amount of tadalafil , hydroxypropyl methyl cellulose as essential polymer base in combination with pectin in a ratio of about 25:1 to about 250:1.

9. An oral fast dispersing or dissolving film according to claim 1, comprising therapeutically effective amount of ondansetron , hydroxypropyl methyl cellulose and maltodextrin as essential polymer base in combination with pectin in a ratio of about 25: 1 to about 250: 1.

10. An oral fast dispersing or dissolving film comprising

a. about 2-50% of tadalafil

b. about 0.2-2% of pectin

c. about 5-80% of hydroxypropyl methyl cellulose.

11. An oral fast dispersing or dissolving film comprising

a. about 2-40% of ondansetron

b. about 0.1-2%) of pectin

c. about 10-50% of hydroxypropyl methyl cellulose

d. about 10-50% of maltodextrin.

12. An oral fast dispersing or dissolving film for delivery of active comprising therapeutically effective amount of an active pharmaceutical agent, wherein said film is bioequivalent to conventional immediate release oral formulations that comprises same amount of said active pharmaceutical ingredient.

13. An oral film according to claim 12, comprising therapeutically effective amount of tadalafil or pharmaceutically acceptable salt thereof, wherein said film is bioequivalent to conventional immediate release oral formulations that comprises same amount of tadalafil or pharmaceutically acceptable salt thereof.

14. An oral film according to claim 12, comprising therapeutically effective amount of ondansetron or pharmaceutically acceptable salt thereof, wherein said film is bioequivalent to conventional immediate release oral formulations that comprises same amount of ondansetron or pharmaceutically acceptable salt thereof.

15. An oral film according to claim 1, wherein said film exhibits an in-vitro release of at least 60% in 5 minutes and at least 75% in 15 minutes.

16. An oral film according to claim 1, wherein said film exhibits a burst strength ranging from about 200 to about 2500 kg/mm and exhibits a tensile strength ranging from about 100 kg/mm² to about 400 kg/mm².

17. A process of preparing an oral film according to any of the above claims, comprising: mixing the active pharmaceutical ingredient, water soluble polymer, film forming polymer, optionally plasticizer, emulsifier and other pharmaceutical excipients to form a multi component matrix and the mixture is drawn into a film by casting or coating.

18. An oral fast dispersing or dissolving film composition as herein above described in the specification.