DESC:FIELD OF THE INVENTION
[0001] The present invention relates to a fast dissolving immediate release sublingual film composition comprising a therapeutically effective amount of an opioid analgesic or its pharmaceutically acceptable salts, one or more of polymer(s), one or more of penetration enhancer(s), one or more of plasticizer(s) and one or more of sweetening agent(s) optionally with one or more pharmaceutically acceptable excipients. The present invention also relates to a process for the preparation of such composition thereof.

BACKGROUND OF THE INVENTION
[0002] Pain, as defined, is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or describe in terms of such damage. Generally pain is experienced when the free nerve endings constituting the pain receptors in the skin as well as in certain internal tissues are subjected to thermal, mechanical, chemical or other noxious stimuli. The pain receptors can transmit signals along afferent neurons into the central nervous system and thence to the brain.
[0003] There are several types of pains. Various pain types include chronic pain, e.g., nociceptive, neuropathic, psychogenic pain, and mixed nociceptive and neuropathic pain. Examples of these types of pain include, but are not limited to, diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, inflammatory bowel disease (IBD) pain, multiple sclerosis pain, post-operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain and cystitis and vulvar vestibulitis and orchialgia, irritable bowel syndrome, premenstrual syndrome pain, pain resulting from burns or chemical injury or sunburn, and bone injury pain.
[0004] Thus, there is a continuing need for analgesic medications able to provide high efficacy pain relief while reducing the possibility of undesirable effects. Non-steroidal anti-inflammatory drugs (“NSAID'S”), including compounds such as ibuprofen, ketoprofen and diclofenac, have anti-inflammatory actions and are useful for the short-term treatment of acute musculoskeletal injury, acute painful shoulder, postoperative pain and dysmenorrhea. However, NSAID'S such as diclofenac produce side effects in about 20% of patients that require cessation of medication. Side effects include, for example, gastrointestinal bleeding and the abnormal elevation of liver enzymes limits the use of such analgesics in severe pain.
[0005] The opioid analgesics are a group of drugs, both natural and synthetic, are employed primarily as centrally-acting analgesics and are opium or morphine-like in their properties. Opioids are the drugs of choice for moderate to severe pain associated with advanced illness. There are several first line oral opioid drugs which include but not limiting to Codeine, Tapentadol, Morphine, Hydromorphine and Oxycodone. These drugs show half-life of 2 to 4 hours with duration of analgesic effect between 4 to 5 hours when given at effective doses.
[0006] Tapentadol, 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol), is a centrally acting analgesic with a dual mode of action: mu-opioid receptor agonism and noradrenaline reuptake inhibition. Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such as hydrocodone, oxycodone, and morphine with a more tolerable side effect profile. Tapentadol is highly soluble drug and its solubility is pH dependent. It is considered as BCS class-1 drug.
[0007] Conventional compositions (i.e. immediate release compositions) for oral administration of tapentadol lead to rapid release of the active ingredient in the gastrointestinal tract resulting in quick onset of action, but at the same time, a subsequent rapid reduction in the action is observed due to short half life (4 hrs) of tapentadol. The immediate release tablets comprising tapentadol marketed by Ortho McNeil Janssen under the brand name of Nucynta® in various strengths.
[0008] Solid oral dosage forms of tapentadol are known from the prior art, for example, WO 02/067651, WO 03/035053, WO 2006/002886, WO 2007/128412, WO 2007/128413, WO 2008/110323, WO 2009/092601, WO 2009/067703, and US 2007-128412.
[0009] WO 2009067703 by Ramesh Sesha discloses pharmaceutical compositions comprising slow release tapentadol hydrochloride in combination with a second analgesic.
[00010] US 2005/0058706 by Johannes Bartholomaeus et al., discloses a slow-release pharmaceutical composition, containing tapentadol or a pharmaceutically acceptable salt thereof in a matrix wherein a peak serum level of the active ingredient is obtained in vivo within 2 to 10 hrs after administration of the composition. It also discloses simulation studies with repeated administration of the pharmaceutical composition at 12 hourly intervals, which showed that, serum levels are achieved and do not fall below 20 ng/ml, so good analgesic efficacy is ensured by twice daily administration.
[00011] However, when tapentadol is given orally, it undergoes extensive first pass metabolism, which leads to achieve low bioavailability (32%). About 97% of the parent compound is metabolized. None of the metabolites contributes to the analgesic activity. Lipid solubility of tapentadol is approximately 2.8, which is comparatively low. Being an opioid analgesic, tapentadol is useful for the treatment of severe pain such as post operative pain, cancer pain etc. In such cases nausea and vomiting is a frequently associated problem and hence poor patient compliance is seen with oral administration. Moreover, for the treatment of breakthrough pain oral formulations are inadequate as it needs at least 45 minutes to absorb after administration, which is not suitable in the treatment of breakthrough pain, as this delay in absorption is typically longer than the episode of breakthrough pain. The maximum serum concentration of tapentadol is typically observed at around 1.25 hours after oral dosing. Further the bitter taste of tapentadol is not patient friendly, which eventually leads to non adherence to the drug therapy.
[00012] Various patents and patent applications have discussed about the non conventional delivery system for opioid compounds. Patent Publication no. WO 2013171146 discusses about a control release oral wafer or film dosage form that contains two layers wherein first layer contains an opioid analgesic and second layer contains mucoadhesive polymeric composition.
[00013] International application publication no. WO2013153145 describes an oral wafer or edible oral film dosage which includes a controlled release layer containing enteric-release beads dispersed in a polymer matrix. The enteric beads contain opioid agonist and are coated with enteric release polymer. The controlled release polymer matrix dissolves or disintegrates following administration of the oral wafer or edible oral film, releasing the enteric-release beads to be swallowed, with subsequent absorption of the active ingredients within the patient's intestines.
[00014] European Patent EP2233134 describes an intra-oral dosage form containing multi portion where one portion contains the pharmaceutically active agent and other contains a component for creating a noticeable organoleptic sensation. Further Patent No. GB 2487007 describes a dosage form for sublingual administration of opioids. It discusses about sublingual liquid spray formulation of opioid analgesic which eliminates the first pass effect of drug in the body and improves bioavailability. However, administration of such dosage form is still a concern for children and geriatrics.
[00015] International application publication no WO2010096045 describes about a dosage form comprising at least one form of tapentadol and at least one opioid antagonist wherein the said antagonist is in amount effective to improve the efficacy and/or reduce the side effects of tapentadol. Further Patent application publication no. WO2011017122 discusses a dosage form comprising Non Opioid Peptide agonist which has to be administered via craniofacial mucosal route.
[00016] There exists need for an alternative dosage form of Tapentadol which overcomes the above problems such as low bioavailablity, gastric irritation, adverse effects etc and moreover provides quick onset of action with reduction of inter-subject variability and improved patient compliance.
[00017] The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

OBJECTS OF THE INVENTION
[00018] The main object of the present invention is to provide a fast dissolving immediate release sublingual film composition comprising a therapeutically effective amount of an opioid analgesic or its pharmaceutically acceptable salts, one or more of polymer(s), one or more of penetration enhancer(s), one or more of plasticizer(s) and one or more of sweetening agent(s) optionally with one or more pharmaceutically acceptable excipients.
[00019] Another object of the present invention is to provide a process for the preparation of such pharmaceutical composition thereof.
[00020] A further object of the present invention is to provide a pharmaceutical composition for the treatment of acute to severe pain.
[00021] Another object of the present invention is to provide a pharmaceutical composition capable of exhibiting immediate drug release profile.
[00022] Another object of the present invention is to provide a pharmaceutical composition capable of delivering drug directly to the blood circulation and achieving rapidly the maximum drug levels in the plasma.
[00023] Another object of the present invention is to provide a pharmaceutical composition capable of avoiding first pass metabolism of drug inside the body.
[00024] Another object of the present invention is to provide a pharmaceutical composition capable of decreasing gastric irritation of active drug.
[00025] Another object of the present invention is to provide a pharmaceutical composition capable of reducing dose frequency and improving patient compliance.
[00026] Still another object of the present invention is to provide a drug delivery system which obviates the disadvantages associated with the known arts.
[00027] Yet another object of the present invention is to provide a process that is technically and commercially feasible.

SUMMARY OF THE INVENTION
[00028] The present invention relates to a fast dissolving immediate release sublingual film composition comprising a therapeutically effective amount of an opioid analgesic or its pharmaceutically acceptable salts, one or more of polymer(s), one or more of penetration enhancer(s), one or more of plasticizer(s) and one or more of sweetening agent(s) optionally with one or more pharmaceutically acceptable excipients.
[00029] The present invention also relates to a process for the preparation of such pharmaceutical composition thereof.
[00030] In an embodiment, the active ingredient in the pharmaceutical composition of the present invention is selected from the group comprising opioid analgesics, more preferably Tapentadol or its pharmaceutically acceptable salts thereof. In a still preferred embodiment the drug is Tapentadol hydrochloride.
[00031] The present invention further relates to a pharmaceutical composition of the present invention, suitable for oral administration.
[00032] In an embodiment of the present invention, the process for the preparation of sublingual film composition comprising the steps of:
i) preparing a clear aqueous polymeric solution by stirring at least one polymer with water.
ii) adding drug into the clear aqueous polymeric solution of step (i) to form a drug polymeric mixture.
iii) adding a plasticizer to the drug polymeric mixture.
iv) keeping aside the mixture of step (iii) to obtain a swollen polymeric mixture.
v) casting the swollen polymeric mixture into an inert platform and drying a cast in hot air oven for suitable number of hours to form a film.
vii) peeling a dried film from the inert platform to form the sublingual film suitable for oral administration.
[00033] According to the present invention, the concentration of therapeutic drug Tapentadol ranges from 5 to 25 % w/v of the pharmaceutical composition; concentration of one or more of polymer(s) ranges from 5 % to 50 % w/v of the pharmaceutical composition, preferably 30 % w/v; concentration of one or more penetration enhancer(s) ranges from 5 % to 10 % w/v of the pharmaceutical composition; concentration of one or more plasticizer(s) ranges from 5 % to 40 % w/v of the pharmaceutical composition, preferably 10 % to 20 % w/v; and concentration of one or more sweetening agent(s) ranges from 5 % to 25 % w/v of the pharmaceutical composition, preferably 10 % to 20 % w/v.

BRIEF DESCRIPTION OF DRAWINGS
[00034] Fig. 1 illustrates in vitro ZERO ORDER RELEASE KINETICS
[00035] Fig. 2 illustrates in vitro FIRST ORDER RELEASE KINETICS
[00036] Fig. 3 illustrates in vitro HIGUCHI RELEASE KINETICS
[00037] Fig. 4 illustrates in vitro PEPPAS RELEASE KINETICS
[00038] Fig. 5 illustrates in vitro HIXSON CROWELL RELEASE KINETICS
[00039] Fig. 6 illustrates ex vivo DRUG RELEASE PROFILE for TAP 1 and 3
[00040] Fig. 7 illustrates ex vivo ZERO ORDER RELEASE KINETICS
[00041] Fig. 8 illustrates ex vivo FIRST ORDER RELEASE KINETICS
[00042] Fig. 9 illustrates ex vivo HIGUCHI RELEASE KINETICS
[00043] Fig. 10 illustrates ex vivo PEPPAS RELEASE KINETICS
[00044] Fig. 11 illustrates ex vivo HIXSON CROWELL RELEASE KINETICS

DETAILED DESCRIPTION OF THE INVENTION
[00045] The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying figures and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein.
[00046] The present invention relates to a fast dissolving immediate release sublingual film composition comprising a therapeutically effective amount of an opioid analgesic or its pharmaceutically acceptable salts, one or more of polymer(s), one or more of penetration enhancer(s), one or more of plasticizer(s) and one or more of sweetening agent(s) optionally with one or more pharmaceutically acceptable excipients.
[00047] A further object of the present invention is to provide a process for the preparation of pharmaceutical composition thereof.
[00048] As used herein, the term “active ingredient” or “active pharmaceutical ingredient” or “drug” or “active drug” means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and are present in the drug product in a modified form intended to furnish the specified activity or effect.
[00049] The term "opioid analgesic" as used herein refers to any material that produces an analgesic effect through modulation of an opioid receptor, whether or not approved by a government agency for that purpose. The term includes all pharmaceutically active forms of the opioid analgesic, including the free base form of the agent, and all pharmaceutically acceptable salts, complexes, crystalline forms, co-crystals, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.
[00050] The term “subject” as used herein refers to a mammal, preferably a human.
[00051] The term "inter-subject variability" as used herein is defined as the variability in response which occurs between subjects in an experiment or in patient population or in a group of people, administered with a drug or a composition. The inter subject variability is represented in the form of coefficient of variation.
[00052] The term "Fast dissolving" or "flash dissolving" means a dissolving within less than 60 seconds and more preferably within less than 30 seconds.
[00053] The term “first pass metabolism of drug” as used herein refers to a process of drug degradation during a drug's transition from initial ingestion to circulation in the blood stream. It is the loss of drug during the process of absorption which is generally related to the liver and gut wall.
[00054] The term "sublingual patch" or "film" as used herein typically refers to a flexible film that provides transmucosal delivery, primarily through the oral epithelium beneath the tongue and delivers the active agent. Such films can be either quick dissolving or dispersing films releasing the active agent immediately or can be films having mucoadhesive properties with the active being released over a period of time.
[00055] The active ingredient in the delivery system of the present invention is preferably Tapentadol or any analogue or derivative of Tapentadol, which exhibits either a pharmacological or a therapeutical activity, which is at least equivalent to that of Tapentadol. Within the scope of the present invention is Tapentadol in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates including the hydrate, anhydrate, complexes thereof etc.). Included is also any analogue, derivative or active metabolite of Tapentadol, pharmaceutically acceptable salts, solvates, complexes and prodrugs thereof.
[00056] The term "pharmaceutically acceptable salts" as used herein refers to describe those salts in which the anion (or cation) does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, they are the pharmacological equivalents of the bases of the compounds to which they refer. Examples of pharmaceutically acceptable acids that are useful for the purposes of salt formation include but are not limited to hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, fumaric, succinic, phosphoric, nitric, maleic, mucic, isethionic, palmitic, tannic and others. The active salt combinations of the active ingredients may be the free acids, bases or as salts having anionic functional groups such as bitartrate, maleate, citrate, chloride, bromide, acetate and sulfate. The source of the functional groups may be natural or synthetic.
[00057] The term “polymer” as used herein refers to natural and synthetic polymers. Examples of preferred polymers are cellulosic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose and its salts and mixtures of two or more thereof; vinyl polymers such as polyvinyl acetate, polyvinyl pyrrolidone; natural polymers such as natural gums like xanthane gum, tragacanth, guar gum, acacia gum, arabic gum; and acrylic acid polymers and copolymers such as carbopol, polycarbophil etc. An embodiment contains about 25 to about 75% w/w of high viscosity hydroxypropyl methylcellulose polymer, preferably about 30 to about 70% w/w of hydroxypropyl methylcellulose (HPMC K15) as the polymer.
[00058] The term "plasticizer" as used herein refers to a chemical entity that, when present, reduces the glass-transition temperature of amorphous polymers. A particular embodiment of the invention incorporates a plasticizer to impart flexibility, enhance elasticity and decrease brittleness. The increased plasticity can be measured by an increased strain elongation of the film. The strain elongation can be measured in a static tension test. In this test the film is subjected to increased tension until the film breaks. The elongation at the breaking point is designated as strain elongation (change in length per unit length). Preferred plasticizers include glycerol, propylene glycol, low molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate, triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutyl sebacate, sorbitol, xanthan, a medium chain triglyceride, polyethylene glycol or carrageenan, castor oil and the like thereof.
[00059] The term "penetration enhancer" as used herein encompasses a substance that can increase sublingual permeation of an active ingredient and thereby enable a transcellular route for transportation of the drug through the buccal epithelium. Certain non-limiting examples of pharmaceutically acceptable penetration enhancers include benzalkonium chloride, cetylpyridinium chloride, cyclodextrins, dextran sulfate, lauric acid/propylene glycol, menthol, oleic acid, oleic acid derivatives, polyoxyethylene, polysorbates, sodium EDTA, sodium lauryl sulfate, sodium salicylate and the like thereof.
[00060] In an embodiment, the sweetening agent is selected from the group comprising glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl- 1-1-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, such as Lo Han Kuo and the like thereof.
[00061] In an embodiment of the present invention, the sublingual films can be prepared by any of the prior art methods including but not limited to, for example, Solvent casting method, Semisolid casting method, Hot melt extrusion method, Solid dispersion extrusion method and Rolling method.
[00062] In a preferred embodiment of the present invention, the method used for the preparation of sublingual films is solvent casting method.
[00063] In a preferred embodiment, the sublingual film is prepared by a process that comprises of the following steps:
i) preparing a clear aqueous polymeric solution by stirring at least one polymer with water.
ii) adding drug into the clear aqueous polymeric solution of step (i) to form a drug polymeric mixture.
iii) adding a plasticizer to the drug polymeric mixture.
iv) keeping aside the mixture of step (iii) to obtain a swollen polymeric mixture.
v) casting the swollen polymeric mixture into an inert platform and drying a cast in hot air oven for suitable number of hours to form a film.
vii) peeling a dried film from the inert platform to form the sublingual film suitable for oral administration.
[00064] In a preferred embodiment of the present invention, stirrer used for stirring in step (i), (ii), and (iii) of the process for the preparation of sublingual film as described herein above is a magnetic stirrer for a time period ranging between 1 minute and 1 hour.
[00065] In another embodiment of the present invention, temperature maintained for step (v) ranges from 20oC to 80oC, preferably 20oC to 60oC, more preferably 40oC.
[00066] In another embodiment of the present invention, the drying in step (v) is performed for about 12 hours.
[00067] In another embodiment of the present invention, the inert platform used in step (v) is preferably a petri dish.
[00068] In a further embodiment of the present invention, the pharmaceutical composition of the present invention optionally comprises at least one carrier selected from the group comprising solubilizers, release modifiers, antioxidants, effervescent agents, humectants, taste masking agent, flavouring agent, coloring agent and the like. There may be one or more carriers used in the preparation of the composition of the present invention. The carrier may be solid or liquid. See, for example, Remington: The Science and Practice of Pharmacy, 1995, Gennaro ed.
[00069] The exact dose of the composition of the present invention required to be administered, may vary from subject to subject, depending on the age, weight, general condition of the subject, the mode of administration, and the like. An appropriate dose is readily determined by one of ordinary skills in the art.
[00070] While certain embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the disclosure. Therefore, it is to be understood that the present disclosure has been described by way of illustration and not limitations.

EXAMPLES
[00071] The present invention is explained in detail in the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare the compounds of the present invention.
[00072] Sublingual films of the present invention were prepared by solvent casting technique using hydroxypropylmethyl cellulose (HPMC) K15, Polyvinyl pyrollidone
[00073] Polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and polyethylene oxide (PEO) in different drug and polymer ratios. Water was used as the solvent and polyethylene glycol (PEG) 400 was used as plasticizer.

Example 1: Preparation of Sublingual films of the present invention
[00074] Sublingual films were prepared by solvent casting technique as per the compositions given in Table 1. The weighed quantity of polymer was taken and dissolved in 10mL water. To this mixture, required quantities of Tapentadol hydrochloride was added with constant stirring. This solution was poured into the petri dish and allowed to dry in hot air oven at 40° C for 12 hrs. After drying it was peeled out and packed in self sealed covers stored in desiccator.

Table 1: Sublingual films of exemplary formulations TAP1 to TAP8

Ingredients TAP1 TAP2 TAP3 TAP4 TAP5 TAP6 TAP7 TAP8
HPMC K15 (mg) 700 1050 350 700
PVP (mg) 350 700 350 700
PVA (mg) 700 1400 350 700
Mannitol (mg) 350 350 350 350 350 350 350 350
Water (mL) 20 20 20 20 20 20 20 20
PEG 400 (mL) 1.2 1.2 0.9 1.2 0.9 1.2 0.9 1.2
1.1 Dose
As per the requirement of petri dish, 700 mg of drug was incorporated in a sublingual film such that each 1*1 cm2 contains 10 mg of drug in every formulation.
1.2 Evaluation of sublingual films:
The prepared sublingual films were evaluated for physico-chemical properties like appearance, surface texture, weight variation, thickness, folding endurance, surface pH and drug content and mucoadhesive properties like swelling index, mucoadhesive strength, in-vitro release studies, ex-vivo release studies were done.
i. Physical appearance:
The films were observed visually for their physical appearance such as colour and transparency.
ii. Surface texture:
The surface texture of the films was evaluated by pressing the film with finger.
iii. Weight variation:
Films of different formulations were taken and weighed by using analytical balance (SHIMADZU) and mean weight of the films was calculated.
iv. Thickness:
Films of different formulations were taken and thickness of the films was measured using screw gauge at different places. The average thickness of the film was calculated.
v. Folding endurance:
The sublingual film was repeatedly folded at 1800 angle of the plane at the same plane until it broke or folded to 300 times without breaking. The number of times the film is folded without breaking is considered as folding endurance value. The mean of three determinations was computed.
vi. Surface pH:
Surface pH of the sublingual film was determined by allowing the film to swell in contact with 1.0mL of pH 6.8 phosphate buffer for 1hr in a watch glass. The surface pH was noted by making the film to come in contact with the pH meter.
vii. Drug content uniformity of films:
The films were evaluated for drug content uniformity. The film was cut in a size of 1x1cm2 and then dissolved in 20mL pH 6.8 phosphate buffer. The drug content was estimated by measuring the absorbance at a wave length of 273nm.
viii. Swelling index:
2.5% agar gel was prepared and poured into a petri dish and allowed to solidify. Sublingual films were weighed individually (W1) and placed in petri dish with the core facing agar gel and allowed to swell. The films were removed at time intervals of 1, 2, 3, 4, 5, 6, 7 and 8 minutes from the petri dish and excess surface water was removed carefully with the tissue paper. The swollen films were then reweighed (W2). The swelling index was calculated according to the following equation
Swelling index = (W2-W1)/W1 × 100
Where,
W1 = dry weight of the film
W2= wet weight of the film
ix. Measurement of mucoadhesive strength:
Detachment force was measured on a modified balance in which the right pan was removed. A plastic beaker was kept in left pan and both the sides were balanced by weights. The sublingual mucosal tissue of porcine was collected from the local slaughter house and stored in ringer solution. The underlying connective tissue was separated and washed with pH 6.8 phosphate buffer. The mucosal membrane was cut and attached to the glass slide with the mucosal side facing outwards using cyanoacrylate glue and this slide was attached to the petri plate, and it was placed on the right side of the balance. The film was attached to the glass slide facing outwards using cyanoacrylate glue. Glass slide was suspended on the right hand side using a non-elastic thread and height of the thread was adjusted. The mucus layer and the film were wetted with pH 6.8 phosphate buffer and the film was fixed to the mucus layer by applying a little pressure with the thumb. This was kept undisturbed for 5 min. On left hand side, water was added slowly in to a plastic beaker with the help of a burette till the film just separated from the membrane surface. The weight of water in grams required to detach the film was noted and was converted into Newton. The mucoadhesive strength was calculated using the formula:
Mucoadhesive force (N) = Mucoadhesive strength × 9.8 / 1000
Example 2: In vitro release studies
In vitro release study was performed in Franz diffusion cell, dialysis membrane was used as a barrier membrane with pH 6.8 phosphate buffer as a medium. Dialysis membrane was soaked for 24 hrs in pH 6.8 phosphate buffer. The films were evaluated for drug release using diffusion cells, dialysis membrane was attached between the donor and receptors compartments. The prepared sublingual films containing drug was placed on the dialysis membrane without any air bubble and maintained at 37 ± 2°C. The receptor compartment was filled with 30 mL pH 6.8 phosphate buffer and hydrodynamics was maintained by stirring with a magnetic bead at 500 rpm. 3 mL sample was withdrawn and replaced with 3 mL fresh pH 6.8 phosphate buffer to maintain volume. The drug release samples were analysed by UV visible spectrophotometer at 273 nm.
Example 3: Ex vivo release studies:
Ex vivo sublingual permeation of tapentadol hydrochloride was studied with fresh porcine sublingual mucosa as a barrier membrane. The sublingual pouch of freshly sacrificed animal was procured from local slaughter house and was used within 2 hrs of slaughter. The sublingual mucosa was excised and trimmed evenly from the sides underlying connective tissue was removed. The membrane was washed with mammalian ringer solution and then with phosphate buffer (pH 6.8). The Ex vivo permeation studies were carried out using the modified Franz diffusion cell at 37ºC ± 0.2ºC. A film of (1 ? 1 cm diameter) each formulation under study was placed in intimate contact with the excised porcine sublingual mucosa magnetic bead was placed in the receptor compartment filled with 30 mL of pH 6.8 phosphate buffer. The cell contents were stirred with a magnetic stirrer and temperature of 37ºC ± 0.2ºC was maintained throughout the experiment. The samples were withdrawn at predetermined time intervals, filtered, diluted suitably, and then analyzed using UV-spectrophotometer at 273 nm.
Example 4: Release kinetics:
Model dependent methods are based on different mathematical functions, which describe the dissolution profile. Once a suitable function has been selected, the dissolution profiles are evaluated depending on the derived model parameters. In order to determine the suitable drug release kinetic model describing the dissolution profile, the nonlinear regression module of Statistica 5.0 was used. In non-linear regression analysis the Quasi-Newton and Simplex methods minimized the least squares. The model dependent approaches included zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, Baker-Lonsdale, Weibull, Hopfenberg, Gompertz and regression models.
Example 5: Results of the In – vitro Studies
The disintegration time was found to be less than one minute for optimized formulations
5.1. Physical appearance and surface texture:
All the films have shown smooth surface and elegant texture with off white colour. The films from all the formulations were translucent and flexible without any sign of crack.

5.2. Weight variation:
The weights of (1x1 cm2) films of HPMC, PVP and PVA were in the range of 40.12 to 60.79 mg whereas PVA, and HPMC in combination with PVP are in the range of 20.51 to 30.62 mg. The films were found uniform in weight. The results are shown in Table 2.
5.3 Thickness:
All the films have uniform thickness throughout and film. Thickness (sentence continuation film thickness) of HPMC, PVP and PVA were in the range of 0.30 to 0.40 mm. The results are shown in Table 2.
5.4 Folding endurance:
The folding endurance was measured manually, films were folded repeatedly until it was broken. Folding endurance was found to be >300 for all the formulations. The results are shown in Table 2.
5.5 Surface pH:
The surface pH of all tapentadol hydrochloride sublingual films was found to be in the range of 6-7. As pH was found similar to that of sublingual cavity, these formulations were suitable for sublingual drug delivery and no mucosal irritation was expected. No significant difference was found in surface pH of different films. The results are shown in Table 2.
5.6. Drug content uniformity:
The drug content (%) varied between the range 97.40 to 99.20% in all the films. This indicates that the drug was dispersed uniformly throughout the film.
The results are shown in Table 2.
Table 2: Physiochemical properties of sublingual films of Tapentadol Hydrochloride
Formulation Weight variation (mg) Thickness
(mm) Surface pH Folding endurance Drug content (%)
TAP 1 40.12 ±0.025 0.34 ± 0.004 6 -7 > 300 99.24±0.121
TAP 2 40.91 ±0.035 0.36 ± 0.004 6 -7 > 300 98.48±0.105
TAP 3 41.03±0.021 0.38 ± 0.004 6 -7 > 300 98.53±0.044
TAP 4 41.87±0.015 0.39 ± 0.004 6 -7 > 300 98.59±0.103
TAP 5 42.37±0.045 0.26 ± 0.004 6 -7 > 300 97.46±0.546
TAP 6 42.95±0.060 0.30 ± 0.004 6 -7 > 300 97.84±0.313
TAP 7 43.55±0.057 0.46 ± 0.004 6 -7 > 300 96.53±0.409
TAP 8 44.32±0.023 0.47 ± 0.004 6 -7 > 300 97.88±0.412

5.7. Swelling studies:
The formulations prepared were evaluated for swelling property. Films prepared with HPMC and PVA without any combination has shown good swelling property and swelling index was increased with increase in concentrations for both the polymers. Formulations prepared with HPMC and PVA has shown high swelling index than PVP, PVA and HPMC combinations. Swelling index was measured up to 10 minutes at regular intervals of 30, 60, 120, 300, 420 and 600 seconds respectively. The results are shown in Table 3.
Table 3: Swelling studies (%) of different formulations
TIME
(second) TAP1 TAP2 TAP3 TAP4 TAP5 TAP6 TAP7 TAP8
30 36.52±1.50 21.16±1.50 25.44±1.50 56.80±1.50 73.61±1.50 80.44±1.50 34.55±1.50 37.41±1.50
60 75.38±1.50 42.05±1.50 28.22±1.50 63.50±1.50 192.70±1.50 220.51±1.50 43.33±1.50 36.60±1.50
120 100.65±1.50 95.71±1.50 42.27±1.50 51.73±1.50 64.80±1.50
300 157.14±1.50 152.14±1.50 58.77±1.50 80.08±1.50
420 168.52±1.50 212.50±1.50 63.11±1.50 81.92±1.50
600 186.59±1.50 242.60±1.50 84.50±1.50

5.8. Measurement of mucoadhesive strength:
Mucoadhesive strength measurement was conducted for all formulations prepared with HPMC, PVP and PVA. From the formulations prepared with HPMC and PVP (1:1), the maximum mucoadhesion strength of 0.0564 N was observed for the formulation TAP 4 where as low mucoadhesive strength of 0.0251 N was observed for the formulation TAP 7. This indicates that mucoadhesive strength of prepared formulations increase with increase in concentration of the polymer and combination of HPMC and PVP gave better mucoadhesion than the single polymer. The optimized formulation of TAP 1 and TAP 3 have mucoadhesive strength of 0.0382±0.005 and 0.0493±0.005 N respectively.
Formulation Mucoadhesive force (N)
TAP 1 0.0382±0.005
TAP 2 0.0421±0.005
TAP 3 0.0493±0.005
TAP 4 0.0564±0.005
TAP 5 0.0257±0.005
TAP 6 0.0275±0.005
TAP 7 0.0251±0.005
TAP 8 0.0274±0.005
Table 4: Mucoadhesive strength

Example 6: Results of the In-vitro Release studies
The results of in vitro dissolution studies on the sublingual films, TAP 1-8 are shown in Tables and plotted in Figures. The results allow for the following observations and inferences.
Formulations TAP 1 to TAP 8 were prepared using HPMC K-15, PVA and PVP. These formulations showed immediate release profile within 30 minutes. It was observed from the in vitro dissolution data that, with increase in concentration of polymer, the release rate was retarded.
The in vitro diffusion studies of the prepared sublingual films revealed that drug release from the films depends on the concentration of polymer used in the formulation.
Formulations of drug: polymer were taken in 1:1 and 1:2 formulations.
The release profiles of formulations TAP 1, TAP 2, TAP 3, TAP 4, TAP 5, TAP 6, TAP 7 and TAP 8 showed drug release of 94.45, 76.23, 99.34, 80.87, 28.02, 17.69, 90.44 and 90.33 respectively for 18 minutes. Formulations TAP 1 and TAP 3 were selected as optimized formulations. Among all other formulations TAP 3 has shown 99.34% drug release for a desired period of 18 minutes which is suitable for design of sublingual films of tapentadol hydrochloride.
Table 5: in vitro dissolution studies:
Time
(min) TAP1 TAP2 TAP3 TAP4 TAP5 TAP6 TAP7 TAP8
0 0 0 0 0 0 0 0 0
2 28.49 30.84 33.40 35.53 14.41 12.90 15.84 12.90
4 46.80 41.64 49.15 46.33 18.63 14.41 36.64 32.72
6 52.44 47.74 62.40 50.56 20.51 14.88 50.74 43.50
8 62.42 49.15 72.81 52.44 21.92 15.31 66.15 50.09
10 68.54 54.31 83.36 52.91 23.33 15.35 74.11 64.64
15 88.59 66.05 93.52 70.91 26.15 17.01 85.42 81.05
18 94.45 76.23 99.34 80.87 28.02 17.69 90.44 90.33
20 99.47 88.31 91.87 30.69 18.16 93.87 98.26
30 98.42 96.10 37.88 24.27 94.03

Example 7: Drug release kinetic modelling:
Various graphs were plotted (Fig. 1 to Fig. 5): cumulative %drug remaining vs. time (zero order kinetic model); log cumulative of % drug remaining vs. time (first order kinetic model); cumulative %drug release vs square root of time(Higuchi model) and log cumulative % drug release vs. log time (Korsmeyer model), time vs cuberoot drug remaining (Hixson crowell).
Different release characterization model was applied on release profile, regression and release constant was calculated. The regression coefficient is used as indicator of best fitting for each of the models considered. The r values of all the formulations from TAP 1 to TAP 8 are higher in case of first order than zero order model, indicating that the drug release is a concentration independent process. Higher r values of Higuchi model indicate the drug release profile is a diffusion related process. Diffusion is related to transport of drug from polymeric matrix to surrounding medium and depends on the drug concentration. Data of in vitro release were fit into different equations and kinetic models to explain the release kinetics of sublingual films.
Zero order, first order, Higuchi, Peppa’s and Hixson crowell kinetic models were used to interpret the release mechanism.
The following plots were made: cumulative %drug remaining vs. time (zero order kinetic model); log cumulative of % drug remaining vs. time (first order kinetic model); cumulative %drug release vs square root of time(Higuchi model) and log cumulative % drug release vs. log time (Korsmeyer model) , time vs cube root drug release (Hixson crowell)
Formulations TAP 1 and TAP 2:
Formulations TAP 1 and TAP 2 prepared using HPMC followed zero order kinetics and case 2 release mechanism based on the release exponent value (n) of the Peppas model. The release exponent values of TAP 1 and TAP 2 formulations were 1.3157 and 1.3419.
Formulations TAP 3 and TAP 4:
Formulations TAP 3 and TAP 4 prepared using HPMC and PVP combination followed first order kinetics and case 2 release mechanism based on the release exponent value (n) of the Peppas model. The release exponent values of TAP 3 and TAP 4 formulations were 1.3898 and 1.4116.
Formulations TAP 5 and TAP 6:
Formulations TAP 5 and TAP 6 prepared using PVA released only 30% of the drug is released in 30 minutes following first order kinetics and case 2 release mechanism based on the release exponent value (n) of the Peppas model. The release exponent values of TAP 5 and TAP 6 formulations were 1.054 and 1.0282.
Formulations TAP 7 and TAP 8:
Formulations TAP 7 and TAP 8 prepared using PVA and PVP combination followed first order kinetics and zero order kinetics and case 2 release mechanism based on the release exponent value (n) of the Peppas model. The release exponent values of TAP 7 and TAP 8 formulations were 1.1412 and 0.9345.
It was found that Formulation TAP 3 followed first order kinetics and erosion mechanism based on the release exponent value of the peppas model and it was further confirmed by the hixson crowell.
Table 6: in vitro release kinetics of TAP 1-8
Formulations Zero order First order Higuchi Peppas Hixson Crowell
K0 r K1 r r N r r
TAP 1 11.59 0.9758 0.2130 0.9198 0.9984 1.3157 0.9957 0.9849
TAP 2 02.88 0.9421 0.1245 0.9395 0.9908 1.3419 0.9844 0.9805
TAP 3 04.96 0.9293 0.2473 0.9535 0.9946 1.3898 0.9932 0.9952
TAP 4 02.80 0.9174 0.1040 0.9696 0.9818 1.4116 0.9682 0.9731
TAP 5 00.98 0.9031 0.0105 0.9925 0.9817 1.054 0.9872 0.9248
TAP 6 00.52 0.8103 0.0062 0.8350 0.9181 1.0282 0.9049 0.8270
TAP 7 03.06 0.8663 0.1057 0.9618 0.9616 1.1412 0.9421 0.9429
TAP 8 04.83 0.9818 0.1821 0.9321 0.9821 0.9345 0.9840 0.9834

Example 8: Ex vivo evaluation
8.1. Ex vivo drug permeation studies:
Ex-vivo drug release studies were done for the formulations TAP 1 and TAP 3. The release rate was decreased in ex vivo studies when compared to in vitro studies.
Table 7: ex vivo diffusion studies
Time in minutes TAP 1 TAP 3
0 0 0
2 59.12 10.76
4 60.72 11.22
6 62.6 12.82
10 27.84 24.94
15 25.4 25.12
20 16.68 27.48
30 18.3 38.36
60 25.98 75.84
90 79.78
Ex vivo Drug Release Profile for TAP 1 And 3 is shown in Fig. 6.
8.2. Ex vivo drug release kinetic modelling:
Various graphs were plotted (Fig. 7 to Fig. 11): cumulative %drug remaining vs. time (zero order kinetic model); log cumulative of % drug remaining vs. time (first order kinetic model); cumulative %drug release vs square root of time (Higuchi model) and log cumulative % drug release vs. log time (Korsmeyer model).
Different release characterization model was applied on release profile, regression value (r) and release constant was calculated. The regression coefficient (r) is used as indicator of best fitting for each of the models considered. The r value of the TAP 1 and TAP 3 followed zero order indicating that the drug release is a concentration dependent process. Higher r value of Hixson Crowell model indicate the drug release profile is erosion related process. Diffusion is related to transport of drug from polymeric matrix to surrounding medium and depends on the drug concentration. Data of ex vivo release were fit into different equations and kinetic models to explain the release kinetics of sublingual films.
Zero order, first order, Higuchi, Peppas and Hixson Crowell kinetic models were used to interpret the release mechanism.
Formulation TAP 3 followed zero order kinetics and erosion mechanism based on the release exponent value of the Peppas model and it was further confirmed by the Hixson Crowell.
ADVANTAGES OF THE INVENTION

[00075] The present invention provides a fast dissolving immediate release sublingual film composition comprising a therapeutically effective amount of an opioid analgesic or its pharmaceutically acceptable salts, one or more of polymer(s), penetration enhancer(s), plasticizer(s) and a sweetening agent optionally with one or more pharmaceutically acceptable excipients.
[00076] The present invention further provides a process for the preparation of such pharmaceutical composition thereof.
[00077] The present invention provides a pharmaceutical composition for effective pain management.
[00078] The present invention provides a pharmaceutical composition capable of exhibiting immediate drug release profile.
[00079] The present invention provides a pharmaceutical composition capable of avoiding first pass metabolism of drug in the body.
[00080] The present invention provides a pharmaceutical composition capable of decreasing gastric irritation of active drug.
[00081] The present invention provides a pharmaceutical composition which capable of reducing dose frequency and improve patient compliance.
[00082] The present invention provides a drug delivery system which obviates the disadvantages associated with the known arts.
,CLAIMS:We claim,

1. A fast dissolving sublingual film composition comprising a therapeutically effective amount of Tapentadol or its pharmaceutically acceptable salts, one or more of polymer(s), one or more of penetration enhancer(s), one or more of plasticizer(s) and one or more of sweetening agent(s) optionally with one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein the opioid analgesic is Tapentadol hydrochloride.

3. The composition of claim 1, wherein concentration of said Tapentadol ranges from 5 to 25 % w/v of the pharmaceutical composition; concentration of said one or more of polymer(s) ranges from 5 % to 50 % w/v of the pharmaceutical composition; concentration of said one or more penetration enhancer(s) ranges from 5 % to 10 % w/v of the pharmaceutical composition; concentration of said one or more plasticizer(s) ranges from 5 % to 40 % w/v of the pharmaceutical composition; and concentration of said one or more sweetening agent(s) ranges from 5 % to 25 % w/v of the pharmaceutical composition.

4. The composition of claim 1, wherein said one or more polymer(s) is selected from the group consisting of cellulosic polymers, vinyl polymers, and acrylic acid polymers and copolymers.

5. The composition of claim 1, wherein one or more polymer(s) is hydroxypropyl methylcellulose polymer.

6. The composition of claim 5, wherein said composition consists of 30 to about 70% w/w of said hydroxypropyl methylcellulose.

7. The composition of claim 1, wherein said one or more of penetration enhancer(s) is selected from the group consisting of benzalkonium chloride, cetylpyridinium chloride, cyclodextrins, dextran sulfate, lauric acid, propylene glycol, menthol, oleic acid, oleic acid derivatives, polyoxyethylene, polysorbates, sodium EDTA, sodium lauryl sulfate, and sodium salicylate.

8. The composition of claim 1, wherein said one or more of sweetening agent(s) is selected from the group consisting of glucose, dextrose, invert sugar, fructose, saccharin and its salts thereof, aspartame, dihydrochalcone compounds, glycyrrhizin, Stevia Rebaudiana, sucralose, sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, 3,6-dihydro-6-methyl- 1-1-1 ,2,3-oxathiazin-4-one-2,2-dioxide, acesulfame and its salts thereof, and Lo Han Kuo.

9. The composition of claim 1, wherein said one or more of plasticizer(s) is selected from the group consisting of glycerol, propylene glycol, low molecular weight polyethylene glycols, phthalate derivatives, triacetine, citrate derivatives, dibutyl sebacate, sorbitol, xanthan, a medium chain triglyceride, polyethylene glycol, carrageenan and castor oil.

10. A process for the preparation of the sublingual film composition of claim 1 comprising the steps of:
i) preparing a clear aqueous polymeric solution by stirring at least said one polymer with water.
ii) adding said Tapentadol into the clear aqueous polymeric solution of step (i) to form a drug polymeric mixture.
iii) adding said plasticizer to the drug polymeric mixture.
iv) keeping aside the mixture of step (iii) to obtain a swollen polymeric mixture.
v) casting the swollen polymeric mixture into an inert platform and drying a cast in hot air oven for suitable number of hours to form a film.
vii) peeling a dried film from the inert platform to form the sublingual film suitable for oral administration.