FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
1. TITLE:
TRANSMUCOSAL PHARMACEUTICAL COMPOSITION OF LEVOCETIRIZINE
2. APPLICANT:
NAME : ALKEM LABORATORIES LIMITED,
NATIONALITY : IN
ADDRESS : CORPORATE OFFICE, ALKEM HOUSE, DEVASHISH,
ADJACENT TO MATULYA CENTRE, S.B. MARG, LOWER PAREL, MUMBAI-400013, MAHARASHTRA, INDIA
3. PREAMBLE TO THE DESCRIPTION:
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION:

FIELD OF THE INVENTION
The present invention relates to a stable transmucosal pharmaceutical composition of Levocetirizine or pharmaceutically acceptable salt thereof and and processes for preparing thereof. This invention more particularly relates to the method of such composition for alleviating associated symptoms of the allergic diseases such as allergic rhinitis and urticaria requiring fast onset of action.
BACKGROUND OF THE INVENTION
The allergic diseases like Allergic rhinitis and urticaria have the major impact on the quality of life of sufferers. Allergic Rhinitis (AR) represents the most common chronic airway disease in the world affecting many individuals.
Common symptoms of AR includes Symptoms include sneezing, runny nose and red, watery, itchy eyes and like which significantly impair the quality of life with the negative effects apparent in all areas of daily living; specifically difficulties with daily activities, reduced sleep quality, daytime fatigue, impaired learning, impaired cognitive functioning, decreased long time productivity, decreased feeling of mental wellbeing, so it impairs work productivity and school performance. The AR can be considered to be a risk factor for the development of asthma and which is based on duration of symptoms of AR and their severity.
Urticaria is also known as hives and it is an outbreak of swollen, pale red bumps or plaques (wheals) on the skin that appear suddenly either as a result of the body's reaction to certain allergens, or for unknown reasons. Hives usually cause itching, but may also burn or sting. If the condition has a duration of less than 6 weeks, it is acute. If it persists for more than 6 weeks, or recurs, it is chronic. Angioedema is often associated with chronic urticaria. Symptoms of the disorder may endure for several months or years.
The most frequent causes of acute urticaria, which may affect up to 15%—25% of all individuals at some stage in their lives, are viral infections (especially affecting the upper respiratory tract), food allergies, and drug adverse reactions. Physical effects, systemic disease, or long-term infection may also lead to urticaria/angioedema.

Histamine has a key role in the pathophysiology of allergic inflammation. After exposure to an allergen, specific antibodies of the IgE type are produced in genetically predisposed individuals. Because of the central role of histamine in allergic responses, many allergic conditions are treated with antihistamines, including allergic rhinitis and urticaria.
From over more than 70 years Antihistamines have been in clinical use and pharmacological characteristics of these agents have been evolving over that time. Second-generation H1 antihistamine Levocetirizine (LCZ) approved in January 2008 and has potentially lesser sedating effects than the other available anti-histaminics. Therefore, Levocetirizine is the treatment of choice for the relief of symptoms of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), and chronic idiopathic urticaria (CIU) in adults and children aged more than or equal to 6 years.
Currently available marketed preparations like Levocetirizine tablet (XYZAL) and Levocetirizine solution (XYZAL) formulations are indicated for relief of symptoms associated with perennial allergic rhinitis and for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria.
Levocetirizine tablet (XYZAL) and Levocetirizine solution (XYZAL) pharmaceutical preparations have Tmax at 0.9 hours and 0.5 hours respectively. The plasma half-life of oral tablet and oral solution in adult healthy subject is about 8 to 9 hours and the mean oral total body clearance for Levocetirizine is approximately 0.63 mL/kg/min.
The onset of action of Levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hour post drug intake. The extent of metabolism of Levocetirizine in humans is less than 14% of the dose. So there is 14% loss of drug because of liver metabolism. Metabolic pathways include aromatic oxidation, N and O-dealkylation, and taurine conjugation, Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms.
US2006083786 relates to the taste masked pharmaceutical composition comprising Levocetirizine for the medical treatment of allergic conditions.

IN1398/DEL/2007 discloses the mouth dissolving tablet of Levocetirizine and its use for the method of treatment of seasonal and perennial allergic rhinitis.
CN102716099B discloses chewable tablet composition for the alleviating allergy symptoms caused by allergic diseases, such as: allergic rhinitis (including allergic eye symptoms), urticaria, angioneurotic edema, contact dermatitis, insect bite, allergic diseases such as dermatitis of the skin and mucous membranes.
Considering the socioeconomic burden of Allergic Rhinitis and Urticaria, due mostly to its impact on the work productivity the treatment of both should be robust and well defined. In acute allergic diseases like Allergic Rhinitis and Urticaria the medication need to have rapid onset of action for faster alleviation of symptoms.
The prior art reference, P. Choudhwy et al, Asian journal of pharmaceutical and clinical research, Vol, 9 discloses Bilayer sublingual tablets of Levocetirizine hydrochloride and Ambroxol HCL wherein, the Levocetirizine hydrochloride layer was formulated by using the ingredients SSG, croscarmellose sodium, MCC, sodium saccharide, Talc, Mg. stearate, Mannitol. Amborxol layer was formulated by using Sg, camphor, Mg. stearate. Further, the bilayer tablet were evaluated for various evaluation parameters including hardness, thickness, friability, drug content uniformity, wetting time, water absorption ratio and disintegration time.
Aparna C. et al.in Asian Journal of Pharmaceutical and clinical research, Vol 8 discloses Sublingual tablet dosage form comprising montelukast sodium and levocetirizine dihydrochloride which was prepared by direct compression method using SSG, CP and CCS as superdisintegrants. The sublingual tablet dosage form comprising Montelukast and Levocetirizine HCL further were evaluated for the physicochemical parameters.
Both prior art references P. Choudhary et al. and Aparna C. et al. are silent on the specific characterisation of sublingual tablet dosage form. Further, from the disclosure of the references person skilled in the art would have understood that the disclosed sublingual tablet dosage form of Levocetirizine would require 60 minutes for maximum drug release. However, many of the available marketed sublingual tablet preparations such as Saphris provides maximum drug release within 5 min.

Despite the above mentioned prior art(s) disclosing various sublingual pharmaceutical formulations of Levocetirizine, there still exists a need for a sublingual pharmaceutical composition of Levocetirizine, which is able to overcome the problems associated with the existing formulations such as physicochemical parameters, while the most one difficult being development of a stable topical formulation, which provides faster onset of action and peak activity in shorter duration of time to alleviate severe allergic conditions; that cannot be address by any of the products claimed in the above stated inventions.
A significant need remains to develop transmucosal pharmaceutical formulations which provide a rapid onset of action for faster relief of the symptoms associated with allergic rhinitis compared to the currently available therapies. Transmucosal route of administration has faster rate of absorption directly into systemic circulation. This also avoids first pass metabolism & thereby improves overall drug concentration achieved.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a transmucosal pharmaceutical composition comprising Levocetirizine or pharmaceutical acceptable salt thereof in association with the pharrnaceutically acceptable excipients.
It is another object of the invention to provide a sublingual pharmaceutical composition comprising Levocetirizine or pharmaceutical acceptable salt thereof in association with the pharrnaceutically acceptable excipients and process for preparing thereof.
It is another object of the present invention to provide sublingual pharmaceutical composition comprising Levocetirizine or pharrnaceutically acceptable salt thereof which has a rapid onset of action.
It is another object of the invention to provide a Sublingual tablet composition comprising
• Levocetirizine or pharmaceutical acceptable salt thereof
• at least one buffering agent
• at least one sweetening agent

• optionally at least one permeation enhancer
It is another object of the present invention to provide a method of preparation of the sublingual tablet composition comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
It is another object of present invention to provide a sublingual film composition comprising
• Levocetirizine or pharmaceutical acceptable salt thereof
• at least one polymer
• at least one buffering agent
• at least one sweetening agent
• optionally at least one saliva stimulating agent
It is another object of the present invention to provide a method of preparation of the sublingual film composition comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
It is another object of the present invention to provide a method of use of such composition for method of alleviating associated symptoms of allergic diseases like allergic rhinitis and Urticaria.
Another object of the present invention is to provide transmucosal composition of Levocetirizine prepared within a pH range of 3 -9 using suitable buffering agents.
SUMMARY OF THE INVENTION
According to the first aspect of the invention, the present invention relates to the pharmaceutical composition for transmucosal administration of Levocetirizine or pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for transmucosal administration comprising Levocetirizine or salt thereof in association with the pharmaceutically acceptable excipients characterised in that the composition has a rapid onset of action compared to the marketed preparations.
In another aspect, the present invention relates to the sublingual dosage form of Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
In another aspect, the present invention relates to the sublingual tablet dosage form comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
In another aspect, the present invention relates to the sublingual film dosage form comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
According to the second aspect of the invention, the present invention relates to the method of preparation of the fast acting pharmaceutical composition for transmucosal administration comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
In another aspect, the present invention relates to the method of preparation of the sublingual tablet dosage form of Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
In yet another aspect, the present invention relates to the method of preparation of the sublingual film dosage form of Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
According to the third aspect of the invention, the present invention relates to the method of using such composition for alleviating associated symptoms of allergic diseases such as allergic rhinitis and urticaria requiring the rapidity of the response.

According to the fourth aspect of the invention, the present invention relates to the sublingual pharmaceutical composition of Levocetirizine prepared within a pH range of 3 - 9 using suitable buffering agents.
In another aspect, the present invention relates to the transmucosal composition of Levocetirizine or salt thereof in association with sweetening and flavouring agents to provide the composition without unpleasant taste.
DESCRIPTION OF THE PRESENT INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to

"the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed
Levocetirizine dihydro chloride [(R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy]] acetic acid dihydro chloride is an orally active Hl-receptor antagonist. It is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C2,H25ClN2O3•2HCl.
The molecular weight is 461.82 and the chemical structure is shown below:

Histamine is responsible of the majority of the early-phase clinical manifestations of allergic diseases, exerting its diverse effects trough different types of specific histamine receptors (H-receptor). Four specific H-receptors are actually known: H1, H2, H3 and H4; these are transmembrane molecules transducing extracellular signals, by way of G-proteins, to an intracellular second messenger system.
Among the four types of H-receptors, the Hl-receptor (H1R) plays the most important role in the pathogenesis of allergic reaction. It is ubiquitous: located on nerve cells, on airway and vascular smooth muscle cells, on endothelial and epithelial cells, on neutrophils, eosinophils, monocytes/macrophages, on dendritic cells, and on T- and B-lymphocytes.
Therefore, histamine release has many clinical manifestations related to the numerous cells that can be involved in the allergic reaction, e.g., itch, pain, increase of the vascular

permeability with edema and hypotension, flushing, headache, tachycardia, bronchoconstriction, reduction in the atrioventricular node conduction time, and impairment of the CNS functions. Additionally, histamine promotes the release of other mediators from immune-competent cells; it increases the cellular adhesion molecule expression, the chemotaxis of eosinophils and neutrophils, the antigen-presenting cell capacity, and other mechanisms of inflammation
Levocetirizine, the active enantiomer of cetirizine, is an antihistamine; its principal effects are mediated via selective inhibition of H1 receptors. Levocetirizine shows a high affinity and a long-lasting occupancy of the H1R; therefore, the strong and sustained pharmacological inhibition of the H1R present on endothelial and vascular smooth muscle cells prevents vasodilatation, edema formation and mucus hypersecretion (Expert Opin. Pharmacother. (2009) 10(14)).
Levocetirizine has a potent and selective antihistamine activity. It has favourable pharmacodynamics and the pharmacokinetics characteristics e.g., high bioavailability and receptor occupancy, limited tissue distribution and a low degree of metabolism. In addition to the anti-histaminic activity, Levocetirizine also has the anti-inflammatory activity that are observed at clinically relevant concentrations and which may enhance its therapeutic benefit._
Levocetirizine has a half-life of 8-9 hours and oral total body clearance of about 0.63 mL/kg/min. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg O.D. dose, respectively. The onset of action of Levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hour post drug intake. The extent of metabolism of Levocetirizine in humans is less than 14% of the dose.
The accumulation ratio following oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/ml ad 308 ng/ml following a single and a repeated 5 mg once daily dose respectively. Food had no effect on the extent of exposure (AUC) of the Levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet and it is achieved 0.5 hour after administration of oral solution.

The extent of metabolism of levocetirizine in humans after oral administration is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms. First pass metabolism greatly reduces the bioavailability of the drug.
Currently available marketed preparations of Levocetirizine like Levocetirizine tablet and Levocetirizine solution (XYZAL) have Tmax longer than 0.5 hours which will lead to delay in onset of response. Delay in onset of action will eventually affects the on demand anti¬inflammatory responses required in many allergic conditions like Allergic Rhinitis, Urticaria and like.
The present invention provides transmucosal pharmaceutical compositions comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable excipients thereof characterised in that the composition of the present invention provides 80% drug release within 5 minute & thereby achieve Tmax at 0.25 to 0.5 hours. And therefore providing faster onset of action within 0.5 hours.
The transmucosal pharmaceutical composition of present invention provides improved and faster alleviation of symptoms associated with allergic diseases like allergic rhinitis and urticaria. The present invention provides transmucosal pharmaceutical composition of Levocetirizine with lesser side effects compared to marketed oral Levocetirizine formulations.
Pharmaceutical composition, in pharmaceutics, "is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product".
The term "stable" as used herein refers to chemical stability of Levocetrizine in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 2%, when the dosage form is kept at 400C /75 %RH and 300C /75 % RH or 25°C ±2°C/60% ± 5% RH for 6 months.

Transmucosal refers to "the route of administration in which the drug is diffused through the mucous membrane. This can refer to inhalation, nasal, sublingual, vaginal, rectal, or ocular routes".
Onset of action means "the time required after administration of a drug for a response to be observed."
Onset of action refers to the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other methods of ingestion such as smoking or injection can take as little as seconds to minutes to take effect.
The determination of the onset of action, however, is not completely dependent upon route of administration. There are several other factors that determine the onset of action for a specific drug, including drug formulation, dosage, and the patient receiving the drug.
The fast acting dosage form for rapid onset of action may be provided by transmucosal delivery dosage form. The transmucosal drug delivery dosage form available in prior art are pulmonary transmucosal drug delivery, nasal transmucosal drug delivery and oral transmucosal drug delivery. The oral transmucosal drug delivery may be provided, for example, by way of the spray, for example by spraying in oral cavity or under the tongue, or by way of rapid melting tablet formulations or by way of placing the dosage form under tongue or effervescent tablet formulations all of which are known to the skilled person in the art.
In preferred embodiment the present invention provides sublingual composition of Levocetirizine or pharmaceutically acceptable salt thereof. In more preferred embodiment the present invention provides pharmaceutical composition for sublingual administration comprising Levocetirizine or pharmaceutically acceptable salt thereof.
Sublingual literally means 'below the tongue*.
In context of the present invention, sublingual dosage form refers to the dosage form that is to be administered via submucosal route that is below the tongue such that the active is absorbed via the blood vessel below and not via the digestive track absorption. As the

sublingual mucosa is highly vascularized having good absorption properties as compared to other mucosal epithelial cell layer, the therapeutic substance gets rapidly absorbed through it so as to allow direct access to systemic circulation and thereby enabling rapid onset of action while overcoming problems associated with other marketed available oral administrations.
In one embodiment, the present invention provides Sublingual Levocetirizine compositions characterised in that the compositions have a rapid onset of action and therefore provides a faster onset of relief compared to other anti-histaminic.
The present invention provides the sublingual Levocetirizine composition characterised in that the sublingual Levocetirizine composition of the present invention is advantageous over the available marketed preparation and offers benefits by reducing time for onset of action, by shifting AUC & Tmax toward left. Sublingual Levocetirizine composition of the present invention provide rapid onset of action over marketed oral preparations.
The composition of the present invention bypasses first pass metabolism because the sublingual route allow drug to be absorbed directly into systemic circulation. Ease of administration for the patients who have difficulty in swallowing such as paediatric, geriatric patients and psychiatric patients, patients who are mentally ill, disabled and uncooperative is another advantage of the sublingual composition of the present invention.
The sublingual levocetirizine composition of the present does not require water for intake and thus provides an alternative to patients with swallowing disorders as a result of extremities and dysphagia and to patients suffering from nausea, such as those patients receiving chemotherapy. The sublingual dosage form of the present invention is more stable, durable and dissolves rapidly compared to marketed conventional dosage forms.
The sublingual Levocetirizine composition of the present invention has an improved dosing accuracy; specifically sublingual tablet and film composition of the present invention not only ensures accurate administration of drugs but also can improve compliance due to intuitive nature of the dosage form and its inherent ease of administration.
Further, as the levocetirizine sublingual composition of the present invention bypasses first pass metabolism, there can be reduction in the dose which can lead to the reduction in side

effects associated with the molecules. The sublingual Levocetirizine composition of the present invention can be unobstructive and can be designed to leave minimal or no residue in the mouth after administration and also provides a pleasant mouth feel.
In one embodiment, the present invention provides sublingual Levocetirizine compositions characterised in that the compositions have a rapid onset of action as compared to other available marketed preparations of Levocetirizine. The present invention provides sublingual Levocetirizine compositions having Tmax at 0.25 to 0.5 and thereby providing faster onset of action within 0.5 hours; preferably within 0.4 hours. In oral levocetirizine with food Tmax was delayed by 1.25 hours & Cmax was decreased by 36%. The Levocetirizine sublingual composition bypass the first pass metabolism as the sublingual route allow the drug to be absorbed directly into systemic circulation. Therefore food will not affect Cmax and Tmax of the levocetirizine sublingual composition of the present invention.
In an embodiment, the invention is suitable for compositions selected from but not limited to sublingual tablet, sublingual film, sublingual spray, sublingual drops and the like.
Sublingual tablet refers to "one that dissolves when held beneath the tongue, permitting direct absorption of the active ingredient by the oral mucosa".
Sublingual film refers to "dissolving film or oral drug strip to administer drug via sublingual route".
In another embodiment the present invention provides Sublingual Levocetirizine compositions characterised in that the composition bypass the first pass metabolism.
In further embodiment the present invention is directed to methods of using such composition for the treatment of allergic rhinitis and Urticaria. Levocetirizine sublingual composition of the present invention provides faster onset of relief from the associated symptoms of allergic diseases like allergic rhinitis and urticaria.
In another embodiment the present invention provides a method for treating a patient suffering from allergic rhinitis and urticaria comprising administering a therapeutically effective amount of Levocetirizine in sublingual composition.

In one embodiment the present invention is directed to method of preparation of sublingual dosage form comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable excipients.
In another embodiment the Levocetirizine sublingual tablet composition of the present invention can be produced by the process available in prior art references. The process available in the prior art references for preparation of tablet dosage form are direct compression, aqueous granulation, Non aqueous granulation, dry granulation (Roll compaction).
In another embodiment, the Levocetirizine sublingual film composition of the present invention can be prepared by the methods such as Solvent casting, Hot- melt extrusion, Semisolid casting.
In another embodiment the Levocetirizine or pharmaceutically acceptable salt thereof is converted to polymorphic form suitable for incorporation in sublingual film composition.
In another embodiment, the Levocetirizine sublingual film composition prepared by solvent casting method wherein the water soluble ingredients dissolved in water and other suitable solvents used for dissolving polymers and to form a clear solution; both the formed solutions then mixed and casted as film on plain surface and further dried to get the film. The obtained film then cut in the desired size.
In yet another embodiment, the Levocetirizine sublingual film composition is prepared by the Hot-melt extrusion method. In this method the solid carrier mixed properly and added in the extruder having heater to melt the mixture. The melt mixture is then added to the selected shape dies and allowed to cool. The cooled film were then removed from dies and was cut in desired size of film.
In another embodiment, the Levocetirizine sublingual film composition is prepared by Semisolid casting method. Herein the Levocetirizine and other water soluble ingredients were added in suitable in quantity of purified water. Suitable solvent used to dissolve insoluble polymer. Both formed solutions then mixed with addition of the plasticizer to get like mass.

Then formed mass is then casted into film in heat controlled drums or dryer. The obtained films then cut in desired size.
In one embodiment the present invention provides pharmaceutical composition characterised in that the composition comprises a therapeutically effective amount of Levocetirizine in the range of 1% to 5%.
In an embodiment of the present invention sublingual compositions of Levocetirizine are administered sublingually that is below the tongue.
In an embodiment the present invention is particularly suitable for the sublingual tablet dosage form of Levocetirizine or pharmaceutically acceptable salt thereof comprising diluents, disintegrants, buffering agents, sweetening agents, flavours, glidents/Iubricants, permeation enhancers and the like.
In another embodiment the present invention is particularly suitable for the sublingual film dosage form of Levocetirizine or pharmaceutical acceptable salt thereof comprising mucoadhesive polymers, plasticizers, surfactant, buffers, sweetening agents, flavours, salvia stimulating agents, colouring agents and the like.
Levocetirizine molecule has three ionizable moieties resulting three pKa values, for carboxylic acid moiety Pka 2.19 and for Nitrogen moiety Pka 2.80 and 8.0.
The inventors of the present invention have found that by adjusting the pH of the composition in the range of 3 -9 will provide maximum absorption of Levocetirizine. The pH of the saliva is 6. 0; this favours absorption of the drug which remain unionised. Therefore pH range of the Sublingual compositions is important for better absorption of drug through oral mucosa. The present invention provides sublingual composition of Levocetirizine prepared within a pH range of 3-9 which provides enhanced absorption of Levocetirizine.
In further embodiment, the invention is directed to sublingual Levocetirizine pharmaceutical compositions characterised in that the composition provides better patient compliance which is devoid of any unpleasant taste.

Pharmaceutically suitable acceptable excipients that may be used according to the present invention include, but are not limited to diluents, disintegrants, buffering agents, sweetening agents, flavours, glidents/lubricants, permeation enhancers and the like.
The suitable diluents that may be use for the formulation of the invention are microcrystalline cellulose, Lactose monobydrate, Mannitol, dicalcium phosphate, Starch 1500, modified starch, silicified microcrystalline cellulose, calcium phosphate powder, screened sucrose carboxymethylcellulose sodium, coprocessed lactose, sorbitol, maltitol, dextrin, xylitol and like.
Suitable disintegrants selected from but not limited to crospovidone, croscarmellose sodium, Sodium starch glycolate, alginic acid, low substituated hydroxypropyl cellulose.
Examples of buffering agents include but not limited to carbonates (i.e., sodium bicarbonate, sodium carbonate), citrates, sodium citrate, gluconates, phosphate, tartrates or its other salts.
Examples of sweetening agent include but not limited to sorbitol, xylitol, mannitol, xylose, ribose, glucose, mannose, sucralose, saccharin powder, sodium saccharin, aspartame, sodium cyclamate, sucrose, dextrose, maltitol solution or any other saccharides.
Suitable flavours may be use for formulation of invention but not limited to cherry, chocolate mint, citrus, berry, vanilla, butterscotch, mint, peppermint flavour, grape flavour, mixed fruit flavour, banana flavour and like.
Examples of glidents/lubricants include but not limited to colloidal silicon dioxide, magnesium stearate, sodium sterayl famarate, talc, sucrose stearate and like.
The formulations of the present invention may comprise one or more saliva stimulating agents. The saliva stimulating agent increases the rate of secretion of saliva that would aid in the faster disintegration of the rapid dissolving formulations. Generally acids which are used in the preparation of food can be utilized as salivary stimulating agents. Citric acid, malic acid, lactic acid, ascorbic acid and tartaric acid are the few examples of salivary stimulants, citric acid being the most preferred amongst them. The acceptable acids will increase patient.

The formulations of the present invention may also comprise mucoadhesive polymers include but not limited to Cellulose derivatives, pullulan, gelatin, hydroxylpropylmethyl cellulose, Hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, xanthum gum, methyl methacrylate co- polymer, hypromellose and the like.
The formulations of the present invention may also comprise plasticizers including but not limited to Glycerine, propylene glycol, polyethylene glycol, sorbitol, triacetin, dibutylpthalate, triethyl citarate and the like.
The formulations of the present invention herein may comprises one or more permeation enhancers. Permeation enhancers are substances that reversibly increase the permeability of the mucosal epithelium to allow the transport of the drug to the blood circulation/lymph system. Permeation enhancers modify the barrier properties of the absorbing cell layer and thus improve trans-membrane flux. These compounds act by increasing cell membrane fluidity, extracting intercellular lipids, interacting with epithelial protein domains, altering mucus structure and rheology.
The buccal penetration can be enhanced by use of various types of permeation enhancers such as bile salts, surfactants, fatty acids and derivatives, glycerides, salicylates, polymers, chelators, ethanol, cyclodextrins, enzyme inhibitors and chitosan etc.
Examples of bile salts include but not limited to Sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium fasidate, sodium glycodeoxycholate, sodium taurodihydrofusidate. Suitable surfactants that may be use for the formulation of the invention but not limited to sodium lauryl sulfate, Brijl-35, lysophosphatidylcholine, dioctyl sodium sulfosuccinate, sodium dodecyl sulphate, laurenth-9, polysorbate-80, polyethyleneglycol-8-laurate, glyceryl monolaurate.
Examples of fatty acids and derivatives includes but not limited to Sorbitan laurate, sodium caprate, sucrose palmitate, lauroyl choline, sodium myristate, palmitoyl carnitine.
Examples of colouring agents include but not limited to FD&C colors, natural coloring agent, pigments such titanium oxide, zinc dioxide and the like.

Examples of glycerides include but not limited to Phospholipids, monohexanoin, medium chain glycerides. Suitable chelators and salicylates include but not limited to Ethylene diamine tetraacetate (EDTA), disodium EDTA, Salicylic acid, sodium methoxysalicylate, aspirin and the like.
Suitable polymers that may be use for the formulations of invention but not limited to Chitosan, polycarbophil, sodium carboxymethylcellulose and their derivatives. Further the formulation of present invention may also comprise other agents that may act as a permeation enhancers includes but not limited to Zonula occluden toxin, poly-1-arginines, soybean derivative glucosides, citicholine, a-acid derivatives, Azonel, cyclodextrins, benzalkonium chloride, phenothiazines, nitric acid donors, menthol.
In an embodiment the stable transmucosal pharmaceutical composition of Levocetirizine or salt thereof for sublingual administration comprises Levocetirizine dihydrochloride in an amount 1-6%, Lactose monohydrate in an amount of 40-50%, Mannitol in an amount of 30-40%, Stearic acid in an amount of 1-10%, Crospovidone in an amount of 1-10%, Sucralose in an amount of 1-3%, Peppermint flavor in an amount of 1-3%, Sodium citrate anhydrous in an amount of 1-3% and Magnesium stearate in an amount of 1-3%.
In an embodiment the stable transmucosal pharmaceutical composition of Levocetirizine or salt thereof for sublingual administration comprises Levocetirizine Dihydrochloride in an amount of 1-6%, Lactose monohydrate in an amount of 40-50%, mannitol in an amount of 30-40%, stearic acid in an amount of 1-10%, crospovidone in an amount of 1-10%, sucralose in an amount of 1-3%, peppermint flavor in an amount of 1-3%, sodium citrate anhydrous in an amount of 1-3%, sodium caprate in an amount of 1-10% and magnesium stearate in an amount of 1-3%.
In context of the present invention the sublingual dosage form having rapid onset of action relates to the sublingual dosage form which has Tmax at less than 0.5 hours, preferably at 0.4 hours. The sublingual dosage form of the present invention provides the maximum plasm concentration of the drug within 0.5 hours of the administration, preferably within 0.4 hours.
Tmax relates the amount of time that a drug is present at the maximum concentration in serum.

The maximum plasm concentration of the drug at specific amount of the time can be determined by the methods available in the prior art references. The available marketed sublingual dosage form such as Saphris which has rapid onset of action, provides maximum release of the drug within 1-10 minutes. The inventors of the present invention have found that for the rapid onset of action the dosage form must provide release of at least 80% of drug within 5 minutes, preferable within 3 minutes. The sublingual dosage form of the present invention when measured in a standard in-vitro dissolution type II apparatus according to the United states pharmacopeia, using a phosphate buffer at pH 6.8 (USP) as a dissolution medium provides release of at least 80% of the active ingredient within 4 minutes, more preferably within 3 minutes.
The term 'release' mean the active ingredient is released from the formulation and dissolved in dissolution medium.
The invention will now be illustrated in more detail by reference to examples showing preferred but not limiting examples.
A: Levocetirizine Sublingual Tablet
Example 1 Table 1

S.No Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Micro crystalline cellulose 5-80%
3. Mannitol 5-80%
4. Crospovidone 1-15%
5. Saccharin powder 0.5-15%
6. Colloidal Silicon Dioxide 0.5-3%
7. Sodium Bicarbonate 0.1-10%
8. Grape Flavor 0.2-5%
9. Magnesium Stearate 0.5-5%
Total weight (%w/w) 100%
Example 2 Table 2

S.No. Ingredients %w/w
1. Levocetirizine dihydro chloride 5%
2. Micro crystalline cellulose 5-80%
3. Mannitol 5-80%
4. Sodium Lauryl Sulfate 0.1-10%
5. Sorbitol 0.5-50%
6. Crospovidone 0.1-30%
7. Saccharin powder 0.5-50\%
8. Sodium Bicarbonate 0.1-10%
9. Citric Acid Anhydrous 0.1-10%
10. Grape Flavor 0.2-5%
11. Sodium Steryl Fumarate 0.1-10%
Total weight (%w/w) 100%
Example 3 Table 3

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Microcrystalline cellulose 5-80%
3. Mannitol 5-80%
4. Crospovidone 0.1-30%
5. Saccharin powder 0.5-50%
6. Sodium Bicarbonate 0.1-10%
7. Sodium Carbonate 0.1-10%
8. Citric Acid Anhydrous 0.1-10%
9. Cherry Flavor 0.2-5%
10. Sodium Steryl Fumarate 0.1-10%
Total weight (%w/w) 100%
Example 4 Table 4

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Microcrystalline cellulose 5-80%
3. Mannitol 5-80%
4. Crospovidone 0.1-30%
5. Saccharin powder 0.5-50%
6. Sodium Bicarbonate 0.1-10%
7. Sodium Carbonate 0.1-10%
8. Citric Acid Anhydrous 0.1-10%
9. Cherry Flavor 0.2-5%
10. Magnesium Stearate 0.5-5%
11. Sodium Steryl Fumarate 0.1-10%
Total weight (%w/w) 100%
Example 5 Table 5

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Microcrystalline cellulose 5- 70%
3. Mannitol 5- 70%
4. Crospovidone 0.1- 15%
5. Saccharin powder 0.5- 5%
6. Sucralose powder 0.5- 10%
7. Sodium Bicarbonate 0.1-8%
8. Citric Acid Anhydrous 0.1-8%
9. Peppermint Flavor 0.2-5%
10. Magnesium Stearate 0.5-5%
Total weight (%w/w) 100%
Example 6 Table 6

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Microcrystalline cellulose 5- 70%
3. Mannitol 5- 70%
4. Saccharin powder 0.5-5%
5. Sucralose powder 0.5- 10%
6. Sodium Bicarbonate 0.1-8%
7. Citric Acid Anhydrous 0.1-8%
8. Peppermint Flavor 0.2-5%
9. Magnesium Stearate 0.5-5%
Total weight (%w/w) 100%
Example 7 Table 7

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Microcrystalline cellulose 5- 70%
3. Mannitol 5- 70%
4. Crospovidone 0.1- 15%
5. Saccharin powder 0.5- 5%
6. Sucralose powder 0.5- 10%
7. Citric Acid Anhydrous 0.1-8%
8. Peppermint Flavor 0.2-5%
9. Magnesium Stearate 0.5-5%
Total weight (%w/w) 100%
Example 8 Table 8

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Micro crystalline cellulose 5- 70%
3. Mannitol 5- 70%
4. Crospovidone 0.1-15%
5. Saccharin powder 0.5- 5%
6. Sucralose powder 0.5- 10%
7. Sodium Bicarbonate 0.1- 8%
8. Citric Acid Anhydrous 0.1-8%
9. Peppermint Flavor 0.2-5%
10. Magnesium Stearate 0.5-5%
11. Hydroxypropyl methylcellulose 0.5-10%
Total weight (%w/w) 100%
Example 9 Table 9

S.No. Ingredients %w/w
1. Levocetirizine dihydrochloride 5%
2. Microcrystalline cellulose 5- 70%
3. Mannitol 5- 70%
4. Crospovidone 0.1- 15%
5. Saccharin powder 0.5- 5%
6. Sucralose powder 0.5- 10%
7. Sodium Bicarbonate 0.1-8%
8. Citric Acid Anhydrous 0.1-8%
9. Magnesium Stearate 0.5-5%
Total weight (%w/w) 100%
The formulations of the present invention can be produced by the process available in prior art references. The process available in the prior art references for preparation of oral tablet dosage

form are direct compression, aqueous granulation, Non aqueous granulation, dry granulation (Roll compaction).
Manufacturing process: The direct compaction was used for the manufacturing the tablets by using following steps-
1. Sifting: The Levocetrizine Dihydrochloride was co sifted with all ingredients except magnesium stearate through suitable mesh then magnesium stearate was sifting through suitable screen.
2. Blending and Lubrications:
The material of step 1 was blended for 15 min in the blender then lubrication was done by addition of magnesium stearate in the blender.
3. Compression:
After blending and lubrication the compression was done by using appropriate tablet tools.
The inventors of the present invention have evaluated the exemplified sublingual tablet composition of Levocetirizine for In-process control parameters like Hardness test, Disintegration time, pH of the tablet in 5ml water. The result is mentioned in Tablet 10 below.
Table 10:

Example no's 1 2 3 4 5 6 7 8 9
Hardness (N) 50-65 70-90 60-75 60-75 60-75 50-65 60-75 50-65 60-75
Disintegration time (sec) 40-50 50-60 50-60 55-70 50-60 55-65 50-60 55-65 55-60
pH of the tab. in 5 ml water 5.1 5.5 8.4 8.5 5.12 5.5 5.2 5.5 5.2
The in-vitro dissolution profile for Example 5 of Levocetirizine sublingual tablet dosage form of the present invention is shown below in Table 11:
Table 11:

Dissolution medium PH 6.8 Phosphate buffer

Dissolution condition USP type 11,900 ml,50 rpm
Formulation code no/batch no Example 5
component Levocetirizine Dihydrochloride(Drug)
Time (min) % of drug release
1 90.00
3 91.00
5 93.00
10 92.00
The sublingual tablet dosage form of the present invention when measured in a standard in-vitro dissolution type II apparatus according to the United states pharmacopeia, using a phosphate buffer at pH 6.8 (USP) as a dissolution medium provides release of at least 80% of the active ingredient within a minutes, preferably within 4 minutes, more preferably within 3 minutes.
B: Levocetirizine Sublingual Film composition:
Example 10 Table 12

S.No. Ingredients Formulation
1 Polyethylene oxide 0.5-80%
2 Hydroxypropyl methyl cellulose 0.5-80%
3 Maltitol 0.5 - 50 %
4 Acesulfame potassium 0.5 - 50 %
5 Lime flavor 0.2 - 5%
6 Citric acid 0.1-15%
7 Sodium citrate 0.1-10%
Example 11 Tablet 13

S.No. Ingredients Formulation
1. Hydroxypropyl methyl cellulose 0.5-80%
2. Citric acid 0.1 - 15%
3. Sodium citrate 0.1-10%
4. Polyethylene glycol 400 0 -20.0%
5. Sucralose 0.5 - 50 %
6. Peppermint oil 0.2 - 5%
7. Water q.s.
Example 12 Table 14

S.No. Ingredients Formulation
1. Polyvinyl alcohol 0.5-60%
2. Citric acid 0.1-10%
3. Sodium citrate 0.1-10%
4. Polyethylene glycol 400 0-20.0%
5. Sucralose 0.5- 5%
6. Peppermint oil 0.2 - 5%
7. Water q.s.
The formulation of the present invention can be produced by the process available in prior art references. The process available in the prior art references for preparation of sublingual film dosage form are solvent casting, hot- melt extrusion, semisolid casting.
Manufacturing process
The formulation of the present invention can be produced by the process available in prior art references. The process available in the prior art references for preparation of sublingual film dosage form are solvent casting, hot- melt extrusion, semisolid casting.
1. Solvent casting method:
1) Take suitable quantity of Purified water, and add all water soluble ingredients , API and stir properly
2) Take suitable quantity of solvent and dissolve suitable polymer and stir to form clear solution.
3) Add step 2 solution to step 1 and mix well under stirring
4) Step 3 material casted as film on plain surface and dried to get the film, which was cut in the desired size of the film which will provide the desired dose.

2. Hot- melt extrusion method:
1) Mix the drug with solid carrier properly
2) Add the step 1 material in extruder having heater, melt the mixture
3) Add the step 2 melt mixture in selected shape dies and allow to cool
4) After cooling film were removed from dies and was cutted in desired size of film which will provide the desired dose
3. Semisolid casting method:
1) Take suitable quantity of Purified water, and add all water soluble ingredients , API and stir properly
2) Prepare solution of acid insoluble polymer
3) Add the step1 solution to step 2 solution with addition of appropriate quantity of plasticizer to get gel mass
4) Step 3 gel mass casted in to film in heat controlled drums or dryer
5) Step 4 films cut in to desired size of film which will provide the desired dose
While preferred embodiments of the invention have been described in detail, it will be apparent to those skilled in the art that the disclosed embodiments may be modified, and it is therefore desired that the present embodiments and examples be considered in all respects as exemplary rather than limiting, illustrative and not restrictive, reference being made to appended claims rather than to the forgoing description.
C. Levocetrizine Dihydrochloride Sublingual Tablet Composition:
Table-15

S.No 1 Ingredients Example 13 Example 14 Example 15

Mg/unit %w/w Mg/unit %w/w Mg/unit %w/w

Levocetrizine Dihydrochloride 5.00 4.17 5.00 4.17 5.00 4.17
2 Micro crystalline cellulose - - 34.00 28.33 - -
3 Lactose monohydrate 55.00 45.83 50.00 41.67 55.00 45.83
4 Mannitol 40.00 33.33 45.00 37.5 43.00 35.83
5 Stearic acid 5.00 4.17 5.00 4.17 5.00 4.17
6 Crospovidone 5.00 4.17 5.00 4.17 5.00 4.17
7 Sucralose 1.00 0.83 1.00 0.83 0.80 0.67
8 Peppermint flavor 1.00 0.83 1.00 0.83 1.00 0.83
Citric acid anhydrous - - - - 0.20 0.17
9 Sodium citrate anhydrous 2.00 0.83 2.00 1.67 4.00 3.33
10 Magnesium stearate 1.00 0.83 1.00 0.83 1.00 0.83
Tablet Weight (Ms) 120.00 100 120.00 100 120.00 100
Example 16 Table 16

S.No. 1. Ingredients Example 16

(With Sodium Caprate)

Mg/unit %w/w

Levocetrizine Dihydrochloride 5 4.17
2. Lactose monohydrate 55 45.83
3. Mannitol 40 33.33
4. Stearic acid 5 4.17
5. Crospovidone 5 4.17
6. Sucralose 1 0.83
7. Peppermint flavor 1 0.83
8. Sodium citrate anhydrous 1 0.83
9. Sodium caprate 5 4.17
10. Magnesium stearate 1 0.83
Tablet Weight (Mg) 120 100
A. Manufacturing process: The direct compaction was used for the manufacturing the tablets by using following steps-

1. Sifting: The Levocetrizine Dihydrochloride was co sifted with all ingredients except magnesium stearate through suitable mesh then magnesium stearate was sifting through suitable screen.
2. Blending and Lubrications:
The material of step 1 was blended for 15 min in the blender then Lubrication was done by addition of magnesium stearate in the blender.
3. Compression:
After blending and lubrication the compression was done by using appropriate tablet tools.
B. Physical parameter of Levocetrizine Dihydrochloride sublingual Tablet 5 mg: The
inventors of the present invention have evaluated the exemplified sublingual tablet composition of Levocetirizine for In-process control parameters like Hardness (N), Thickness (mm) and Disintegration time (sec).
Table 17

Physical parameter Example: 13 Example: 14 Example: 16 Example: 15
Description White to off-white round tablet White to off-white round tablet White to off-white round tablet White to off-white round tablet
Hardness (N) 45N-60N 47N-55N 48N-58N 40N-53N
Thickness(mm) 2.55 mm -2.57 mm 2.59mm-2.60 mm 2.54 mm -2.60 mm 2.60 mm-2.69mm
Disintegration time (sec) 90 sec -100 sec 95 sec -00 sec 60 sec - 90 sec 50 sec - 70 sec
All the physical and chemical parameters were found satisfactory.
C. Comparative In-vitro Dissolution Profile of Xyzal (immediate release oral tablet) tablet and Test tablets:
Example 13 and Example 14

Table 18:

Time points Xyzal (Levocetrizine Dihydro chloride-immediate release oral) Tablet 5 mg Levocetrizine Dihydro chloride sublingual Table 5 mg
Batch No 19C105 Example 13 Example 14
2min 12.9 85 77
5Min 90.5 87 91
8Min 94.6 87 91
11Min 95.3 87 90
15 min 94.9 95 91
Comparative drug release data of immediate release oral tablet versus sublingual tablet shows faster drug release for sublingual tablet compared to immediate release oral tablet. All the parameters were found satisfactory.
D. Comparative In-vitro Dissolution Profile: Example 16
Product Name: Levocetrizine dihydrochloride sublingual Tablet 5 mg
Medium : Water
Volume : 900 mL
Apparatus : Paddle
Speed : 50 RPM
Time : 2, 5, 8,11,15, minutes
Temperature : 37°C ± 0.5°C
E. Comparative In-vitro Dissolution Profile of Xyzal tablet (immediate release oral tablet) and Test
tablets: Example 16
Table: 19

Time points Xyzal (Levocetrizine Dihydro chloride-
immediate release oral) Tablet 5 mg Levocetrizine dihydrochloride sublingual Table 5 mg
Batch No 19C105 Example 16
2 min 12.9 83
5 Min 90.5 85
8 Min 94.6 85
11 Min 95.3 86
15 min 94.9 85
Comparative drug release data of immediate release oral tablet versus sublingual tablet shows faster drug release for sublingual tablet compared to immediate release oral tablet. All the parameters were found satisfactory.
F. Stability Data: stability condition at 40°C ±2°C/75% ± 5% RH
Table 20

Stability Data- Accelerated condition
Product Nam e: Levocetrizine dihydro chloride sublingual Tablet 5 mg
Batch No Example 13
Pack Size 60,s bottle
Packing HDPE bottle with silica gel with Cap Storage 40°C ±2°C/75% ± 5% RH

Tests Initial 6 Month
Description White to off-white round tablet White to off-white round tablet
Hardness (N) 45N-60N 50N-60N
Thickness(mm) 2.55 mm - 2.57 mm 2.56 mm - 2.57 mm
Disintegration time (sec) 90 sec-100 sec 80 sec-100 sec
pH of Tablet in 5ml of purified water 3.95 4.15
Organic Impurities (by HPLC, w/w) Specification as per ICH Initial 6 Month
Chlorobenzhydryl piperazine Not More than 1.0% 0.087% 0.348%
Levocetirizine Amide Not More than 1.0% ND 0.258%
Any other individual Not More than 0.4% 0.130% 0.338%

impurity
Total Impurities Not More than 2.0 % 0.322% 1.233%
ND - Not detected
Stability data Levocetrizine Dihydrochloride sublingual tablet indicate that the drug product is stable in selected pack primary pack, for Accelerated condition (40°C ±2°C/75% ± 5% RH). All the parameters were found satisfactory.
G. Stability Data: stability condition at 25°C ±2°C/60% ± 5% RH
Table 21

Stability Data- Long term condition
Product Nam >.: Levocetrizine dihydrochloride sublingual Tablet 5 mg
Batch No Example 13
Pack Size 60,s bottle
Packing HDPE bottle with silica gel with Cap Storage 25°C ±2°C/60% ± 5% RH

Tests Initial 6 Month
Description White to off-white round tablet White to off-white round tablet
Hardness (N) 45N-60N 47N-55N
Thickness(mm) 2.55 mm-2.57 mm 2.55 mm - 2.60 mm
Disintegration time (sec) 90 sec-100 sec 70 sec-90 sec
pH of Tablet in 5ml of purified water 3.95 4.10
Organic Impurities (by HPLC, w/w) Specification as per ICH Initial 6 Month
Chlorobenzhydryl piperazine Not More than 1.0% 0.087% 0.124%
Levocetirizine Amide Not More than 1.0% ND 0.020%
Any other individual impurity Not More than 0.4 % 0.130% 0.204%
Total Impurities Not More than 2.0% 0.322% 0.504%
ND - Not detected
Stability data Levocetrizine dihydrochloride sublingual tablet indicate that the drug product is stable in selected pack primary pack, for Long term condition (25°C ±2°C/60% ± 5% RH). All the parameters were found satisfactory.

H. Buffer Capacity Estimation for Proposed Sublingual Tablet:
Levocetrizine molecule has three ionizable moieties resulting three pKa values, for carboxylic acid moiety Pka 2.19 and for Nitrogen moiety Pka 2.80 and 8.0,
The inventors of the present invention have found that by adjusting the pH of the composition in the range of 3 -7 will provide maximum absorption of Levocetirizine. The pH of the saliva is 6. 0; this favours absorption of the drug which remain unionised. Therefore pH range of the Sublingual compositions is important for better absorption of drug through oral mucosa. The present invention provides sublingual composition of Levocetirizine prepared within a pH range of 3-7which provides enhanced absorption of Levocetirizine.
I. Procedure for Buffer Capacity Estimation of Sublingual Tablet:
As average volume of saliva in humans is around 5 ml and it will vary as per medical condition and individual to individuals so pH of tablet were determined in 5 ml purified water.
Table 22

Batch No. ZUBSOLV®
(buprenoiphine
and naloxone)
sublingual tablet Example 15 Example 14 Example 16
pH in 5 mL purified water 5.22 4.80 4.70 5.60
pH in 10 mL purified water 5.34 4.83 4.90 5.71
pH in 15 mL purified water 5.39 4.85 5.60 5.80
pH in 20 mL purified water 5.48 4.86 5.90 5.91
As per above pH data it was observed that after increasing 4 times purified water volume pH of composition well within the pH 3 to 7 so drug remains in unionized form so Therefore pH range of the Sublingual compositions is important for better absorption of drug through sublingual mucosa. All the parameters were found satisfactory.
J. Comparative In-vitro release test (TVRT) data:
Table no: Comparative IVRT drug release data of immediate release tablet versus sublingual tablet: Example 14

Table 23

Product Xyzal (Levocetrizine Dihydrochloride-immediate release Oral) Tablet 5 mg Levocetrizine Dihydro chloride Sublingual Table 5 mg
Batch no Xyzal Tab (19C105) Example 14
Time min Cumulative Diffusion (μg/cm2) Cumulative Diffusion (μg/cm2)
5 10.16 9.28
15 26.06 41.22
30 49.41 157.78
45 80.55 437.41
60 109.35 653.39
90 176.09 960.88
120 251.40 1117.37
Comparative drug release data of immediate release tablet versus sublingual tablet shows faster cumulative Diffusion for sublingual tablet compared to immediate release tablet. All the parameters were found satisfactory.
K. Comparative IVRT drug release data of immediate release tablet versus sublingual tablet: Example 13, Example 14 and Example 16
Table 24

Time points Xyzal
(Levocetrizine
Dihydrochloride-
immediate release Oral)
Tablet 5 mg Levocetrizine dihydrochloride sublingual Table 5 mg
Batch No 19C105 Example 13 Example 14 Example 16
2 min 12.9 85 77 83
5 Min 90.5 87 91 85
8Min 94.6 87 91 85
11 Min 95.3 87 90 86
15 min 94.9 95 91 85
Comparative drug release data of immediate release tablet versus sublingual tablet shows faster drug release for sublingual tablet compared to immediate release tablet. All the parameters were found satisfactory.

While preferred embodiments of the invention have been described in detail, it will be apparent to those skilled in the art that the disclosed embodiments may be modified, and it is therefore desired that the present embodiments and examples be considered in all respects as exemplary rather than Iimiting,illustrative and not restrictive, reference being made to appended claims rather than to the forgoing description.

CLAIMS:
1. A stable transmucosal pharmaceutical composition for a sublingual administration comprises Levocetirizine or pharmaceutical acceptable salt and one or more pharmaceutically acceptable excipients.
2. A stable Sublingual tablet composition comprises Levocetirizine or pharmaceutical acceptable salt thereof as in claim 1 comprises at least one buffering agent, at least one sweetening agent and optionally at least one permeation enhancer.
3. A stable sublingual tablet composition as in claim 2 comprises buffering agent selected from group consisting of carbonates (i.e., sodium bicarbonate, sodium carbonate), citrates, sodium citrate, gluconates, phosphate, tartrates or its other salts and/or combination thereof, the permeation enhancers selected from group consisting of synthetic bile salts, surfactants, fatty acids and derivatives, glycerides, salicylates, polymers, chelators, ethanol, cyclodextrin, enzyme inhibitors, chitosan and/or combination thereof.
4. A stable sublingual film composition comprises levocetirizine or pharmaceutical acceptable salt thereof as in claim 1 comprises at least one polymer, at least one sweetening agent and optionally at least one saliva stimulating agent.
5. A stable sublingual film composition as in claim 4 comprises polymers selected from group consisting of Cellulose derivatives, pullulan, gelatin, hydroxylpropylmethyl cellulose, Hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, xanthum gum, methyl methacrylate co- polymer, hypromellose and combination thereof,
6. A stable sublingual pharmaceutical composition of Levocetirizine as in claim 1 has a pH range of within 3 -9.
7. A stable transmucosal pharmaceutical composition of Levocetirizine or salt thereof as in claim 1 comprises excipients selected from group consisting of but not limited to polymer, buffering agents, saliva stimulating agents, sweetening agents, permeation

enhancers, surfactants, disintegrants, colouring agents, diluent, flavouring agents, lubricant, plasticizers and combination thereof.
S. A stable transmucosal pharmaceutical composition of Levocetirizine for a sublingual administration as in claim 1 provides a rapid onset of action.
9. A stable transmucosal pharmaceutical composition for a sublingual administration as in claim 1 comprises a dosage form selected from a tablet, film/strips, spray and drops or combination thereof.
10. A stable transmucosal pharmaceutical composition of Levocetirizine for sublingual administration as claimed in claim 1 provides a rapid onset of action for alleviating associated symptoms of allergic diseases like allergic rhinitis and Urticaria.