Form 2
The Patents Act, 1970
COMPLETE SPECIFICATION
(Section 10)
NOVEL PHARMACEUTICAL DOSAGES FORM, IN PARTICULAR,
ORAL STRIP OR THIN FILM FORM OF ACTIVE CETIRIZINE
DIHYDROCHLORIDE THROUGH THE NOVEL PROCESS FOR
MANUFACTURING THE SAME.
Applicant:
Ankur Drugs & Pharma Limited
C-306, Crystal Plaza, Andheri Link Road
Andheri (W), Mumbai - 400 053
Maharastra, India
An Indian National
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to the field of a novel pharmaceutical oral dosage form containing cetirizine dihydrochloride of ease and rapid dissolution and of bitter taste masking in form of strips or thin films and a process for its preparation.
BACKGROUND/PRIOR ART
Cetirizine is a selective H1-receptor antagonist used to treat allergic rhinitis and chronic idiopathic urticaria, and as a treatment adjunct in asthma. It is a racemic mixture of levo- and dextro-form, but levo-form is active. Cetirizine is a generic name for 2- [2- [4- [ (4-chlorphenyl) phenylmethyl]-l- piperazinyl] ethoxy] -acetic acid and is typically provided as a dihydrochloride salt. The hydrochloride salt of cetirizine is a white powder freely soluble in water, practically insoluble in acetone and dichloromethane; administered orally and currently prescribed for the treatment of seasonal allergies in patients aged 2 years and older. The current commercial products are available as a white, film-coated, immediate release oral tablet in 5 and 10 mg. A strengths and a sweet flavored syrup containing cetirizine hydrochloride at a concentration of 1 mg/ml is available for pediatric use. There have been continuous efforts in developing a dosage form of cetirizine dihydrochloride to meet various patient compliances from time to time a few of which are as under.
US 2006127479 discloses a taste masked pharmaceutical composition comprising: (a) a core comprising a bitter tasting drug, such as cetirizine dihydrochloride; and (b) a coating comprising a pharmaceutically acceptable cationic co-polymer based on mono- or dialkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, wherein the alkyl group independently has 1 to 6 carbon atoms, wherein said coating is applied to the surface of said core. The
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taste masked pharmaceutical compositions of the invention may be prepared without using an organic solvent or a cyclodextrin.
WO 2006061700 provides a resinate of Cetirizine or its pharmaceutically acceptable salts or its enantiomers or their salts such as Levocetirizine Dihydrochloride, fast disintegrating and or quick release pharmaceutical compositions containing the resinate and the process for the preparation of the said resinate and its composition. Preparation of resinate and composition comprising resinate is carried out preferably in aqueous solvents.
European patents Nos. 058,146 ; 294,993 ; and 357,369 ; and also WO 92/02212 describe cetirizine formulations for the controlled or continuous release of cetirizine in the form of tablets and capsules. Oral formulations in the form of a cough syrup are disclosed in WO 94/08551.
For example, U. S. Pat. No. 4,650, 663 discloses the preparation of an oral pharmaceutical delivery system in which an unpleasant tasting anti- tussive such as noscapine, carbetapentane citrate or clophedianol hydrochloride is adsorbed onto magnesium silicate flakes and incorporated into a chewable tablet or lozenge. The adsorbate allegedly masks the bitter taste to an almost negligible level to encourage better patient compliance. US 6,027, 746 discloses a soft chewable gelatin capsule having incorporated therein a drug dispersed in an oral suspension comprising a medicament adsorbate which masks bitter or bad-tasting pharmaceutical actives (such as antihistamines, decongestants and the like).
US 6,270, 790 discloses a soft, convex-shaped compressed chewable tablets. Active agents having a bitter or bad taste are masked by coating the drug with a 90: 10 to 50: 50 polymer blend of cellulose acetate or cellulose acetate butyrate and polyvinyl pyrrolidone or hydroxypropyl cellulose. However, coatings
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require an additional manufacturing step which adds to the manufacturing costs of the tablet.
Another known method for masking the taste of active ingredients consists of forming an inclusion complex between the active ingredient and a cyclodextrin. In this case, the masking of the taste results from the trapping of the active ingredient, which cannot be released while it is in the mouth. The use of beta-cyclodextrin with cetirizine is described in WO 99/01133.
Tablets and pills are well known. They are generally the preferred vehicles for oral administration of both prescription and over the counter (OTC) medications. There are certain situations, however, in which the use of tablets or capsules or pills is undesirable. For example, individuals with laryngeal inflammation or esophageal disorders may have difficulty swallowing. In other cases there is no liquid available to aid swallowing. Small children often find it difficult to swallow pills and/or may choke in the attempt. An alternative to tablets and pills is the use of liquid medicaments, e.g., elixirs and syrups. Liquid medicaments have their own drawbacks, however, including imprecise dose measurement and, in the case of oral administration to young children, loss of some or the entire medicament via deliberate or accidental rejection. An ideal alternative would be a solid dosage form that can be administered orally, which rapidly disperses/dissolves in the mouth without bitter taste, and hence does not require great effort in swallowing. Such an idealized approach minimizes the possibility of rejection, if administered to a young child, and yet remains stable in composition and structure over a reasonable period of time, i.e. having adequate shelf life.
One of the drawbacks to oral delivery systems however, is the situation where the drug to be administered is bitter, bad-tasting, odorous or in some
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manner unpleasant especially to children. Many efforts have been made in the past to"tastemask"these compounds either through elaborate flavor and/or sweetener delivery systems, adsorption of the drug within another material or by encapsulation with a polymer, fat, carbohydrate or other like material. These taste-masking methods basically prevent the bitter tasting. There still exists a need for a palatable formulation for cetirizine medicaments that assist in compliance especially with children.
So, any pharmaceutical formulation with a pleasing taste would definitely be preferred over a competitor's product and would translate into better compliance and therapeutic value for the patient and more business and profits for the company. The desire of improved palatability in these products has prompted the development of numerous formulations with improved performance and acceptability. Always it is very much inconvenient to take oral dosage form of bitter taste due to bitterness of the drugs.
The above-discussed prior arts address mostly a pharmaceutical formulation containing cetirizine dihydrochloride in tablet, capsule, syrup or liquid form (for I.V. purpose) for meeting patient compliance. Use of disintegrants are also described in the tablet form for rapid release of cetirizine dihydrochloride. Patients are in need of a formulation containing cetirizine dihydrochloride that can deliver the medicinal value of cetirizine dihydrochloride at a very fast rate without bitter taste. It intends to increase the plasma concentration in blood in a short duration to get fast relief. Some times and also continuous administration of cetirizine dihydrochloride is not advisable as it leads to other side effects. It is desirable to take the required dosage form at the time of need only. The aim of our invention is based on a solution to the above discussed problems which are as follows: (i) Our effort and research findings are of worth in this respect and we have formulated a pharmaceutical composition comprising cetirizine
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dihydrochloride as active ingredient in form of thin film or strip. The main theme of the invention is a pharmaceutical composition containing cetirizine dihydrochloride available in form of thin film or strips without addition of disintegrants and bitter taste masking properties to meet patient compliance, (ii) Cetirizine dihydrochloride also taste very bitter if given sublingually. The conventional solution for masking of bitter drugs also appears in the way of a cover made of rice starch. Thin wafers of boiled rice mashie are made and the bitter drug with its formulation is enclosed in between and becomes easy to administer. However, the masked tablet dosage gets dissolved in the digestive system and takes time for release of the drug. This approach some time fails to deliver the drug immediately whenever required. Administration of such masked tablets especially becomes inconvenient in case of children who cannot easily swallow the tablet. Encountered with such shortcomings a novel dosage form containing cetirizine dihydrochloride as pharmaceutical active in form of thin film or oral strip with accuracy of dosing is disclosed. In order to avoid the bitter taste of cetirizine dihydrochloride the drug in the dosage form sweeteners like maltodextrin, sucralose, sorbitol and the like are added during formulation of the strip or thin film along with flavours and colours. This dosage form works wonderfully being easily and rapidly dissolvable, easy to administer and gives fast relief to patients. Again by this dosage form a very accurate dosing required is attained immediately. For attaining such dosage form, a very specific manufacturing process employing a specially designed apparatus is utilised, (iii) Each of these dosage forms has their drawbacks that limit their usefulness. A dosage form containing cetirizine dihydrochloride in form of thin film or strip that enhances better dissolution properties and consequently immediate and hence makes better bioavailability has never been discussed. The dissolution profile achieved by the present invention is less than about four minutes, preferably less than about three minutes, more preferably in less than about one and half minutes and most preferably in less than about twenty or about one minutes.
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OBJECTIVE OF THE INVENTION
The main objective of the invention is formation of a pharmaceutical dosage form containing effective amount of cetirizine dihydrochloride in the form of a thin film/strip.
Another objective of the invention is formation of the dosage form of cetirizine dihydrochloride to suppress its bitter taste and availing ease dissolution in the mouth.
Further more objective of the invention is to achieve a pharmaceutical dosage form of cetirizine dihydrochloride that finds easy administration, very fast acting and easy acceptability in patients.
One more objective of the present invention is to make a dosage form containing cetirizine dihydrochloride as active in thin film form without using disintegrating agents.
One further more objective of the invention is to devise a process for manufacturing the dosage form containing as active ingredient.
SUMMARY OF THE INVENTION
The present invention discloses a novel pharmaceutical oral dosage form of cetirizine dihydrochloride in form of thin strip/film. Other pharmaceutical adjuvants to improve the properties of the film/strip is disclosed including adding sweeteners and flavours to suppress the bitterness of cetirizine dihydrochloride.
The very delicate dosage form requires special provision for manufacturing via specially designed apparatus and that is adopted in order to carry out the invention.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel pharmaceutical oral dosage form of cetirizine dihydrochloride for easy and rapid dissolution and of bitter taste masking in the form of strips or thin films and a process for their preparation. The pharmaceutical dosage form comprises different components in their respective proportions to add the properties to the dosage as desired to find out a technical solution to the existing problems. The active ingredients i.e. cetirizine dihydrochloride utilised for the in invention is generally bitter in taste. The applicant has come out with a solution of masking the bitter taste of this active ingredient as well as providing easy dissolution and rapid availability of the active ingredient in the dosage form. Conventional ingredients like sweeteners; plasticizers, cellulose base, flavours and colours are provided in the dosage form.
In a preferred embodiment, of the present invention the pharmaceutically active substance i.e. cetirizine dihydrochloride is present in an effective amount as per the dosage form recommended. Once the oral strip or thin film is formed it works with accuracy of dosing required.
In another embodiment, of the present invention, an accurate and sequential process to obtain the end product is devised controlling various parameters involved during formation of the oral strip or thin film.
Yet, in another embodiment, of the invention formation of thin film or strip with accurate dosing is covered which is a very critical task. An apparatus/machine of very high accuracy and precision is implemented during the process operated without employing disintegrating agents in the formulation.
Cetirizine dihydrochloride that taste bitter is exploited for the present invention in an effective amount as per dosage strength.
Since the said drug tastes bitter putting it as such into the strip/ thin film serves no purpose at all. To suppress the bitterness of the drug sweetness are added in quantitative amount. The sweetness like maltodextrin, sucralose, sorbitol
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or mixture thereof in required quantity can be incorporated alone or in combination with.
Other important component of the formulation is cellulose, which is used as base material. The very specific types of base materials are hypromellose, hydroxypropyl methylcellulose, hydroxy propyl cellulose, pregelatinised starch or microcrystalline cellulose. The base material can be used alone or in mixture with others based on the conditions during formulation of dosage.
In order to improve/develop the properties of the strip thin film of the dosage form, well known plasticizers like polyethylene glycol, polypropylene glycol or their mixture is present in required amount. To achieve capacity in the strip/thin film, commercial grade inactive titanium dioxide is provided to the dosage form in required amount.
Since the strip/thin film which contains cetirizine dihydrochloride that tastes bitter, presence of sweetness can't work only and may not meet patient compliance. It is very much important to put flavours and approved colours of desirable amount.
Following are the components in the dosage form in their respective proportions.

Thin film/strip Wt.% in the composition
cetirizine dihydrochloride in the strip Therapeutically effective amount
Base material 20-75
Sweetness 25-45
Plasticizers 7-15
Titanium Dioxide 45-60
Flavours & colours Quantity desired for acceptability and best taste
By the terms "effective amount" or "therapeutically effective amount" of an agent as provided herein are meant a nontoxic but sufficient amount of the agent to
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provide the desired therapeutic effect. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, and the like. Thus, it is not possible to specify an exact "effective amount." However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
We also compared the dissolution rate of the thin film or strip of the formulation of the present invention (available in the Table of the specification) with commercially branded/available tablets in the market. Dissolution profiles were performed in a dissolution apparatus with paddles. Thin strips containing cetirizine dihydrochloride of the present invention and branded tablets were incubated for 15 minutes. From both the samples liquid was withdrawn at required interval of times for analytical purpose and passed through a 0.45 urn filter and analysed by HPLC, with detection at 265 nm. FIGURE 1 presents the dissolution profiles obtained for both formulations. The points represent the average value obtained for 6 thin films (present invention) and tablets (commercially available) of each formulation. The data show that after 60, 120, 180, 240 seconds of incubation the thin film dosage form of the present invention containing cetirizine dihydrochloride released 30%, 50%, 10% and 82% of the active ingredient, respectively, whereas the commercially branded tablets released, after the same times, only 10%>, 20%, 35%> and 50%. With this experiment, we concluded that the dissolution of cetirizine dihydrochloride formulations of the present invention is faster than the one of the conventional tablets existing on the market. These results suggest that the pharmacological effect produced by the administration of the formulations of the present invention seems to be more rapidly achieved than with conventional tablets.
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Table 1:

Invented product containing cetirizine dihydrochloride as drug of dosage 1 mg Tablet containing cetirizine dihydrochloride as a drug of dosage 1 mg available in brand names of immediate release type.
Time in seconds Release profile (%) Time in seconds Release profile (%)
0 NIL 0 NIL
60 30 60 2
120 50 120 10
180 70 180 20
240 82 240 35
300 90 300 50
360 100 360 65
Table 2:

Invented product containing cetirizine dihydrochloride as drug of dosage 2 mg Tablet containing cetirizine dihydrochloride as a drug of dosage 2 mg available in brand names of immediate release type.
Time in seconds Release profile (%) Time in seconds Release profile (%)
0 NIL 0 NIL
60 28 60 2
120 49 120 9
180 67 180 18
240 80 240 32
300 90 300 48
360 100 360 63
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Table 3:

Invented product containing cetirizine dihydrochloride as drug of dosage 5 mg Tablet containing cetirizine dihydrochloride as a drug of dosage 5 mg available in brand names of immediate release type.
Time in second Release profile (%) Time in-second Release profile (%)
0 NIL 0 NIL
60 25 60 2
120 48 120 9
180 65 180 17
240 80 240 30
300 90 300 45
360 100 360 62
"In vivo" trials have shown that the thin films/strips forms of the invention provide more rapid absorption than commercial formulations containing cetirizine dihydrochloride. A group of patents were used as volunteers and time taken by them to reach the maximum blood level concentration of the drug taking 2 mg tablets available commercially and with a strip containing 2 mg cetirizine dihydrochloride of the present invention were compared. The time needed to reach the maximum blood level concentration was found to be faster in case of the invented thin film than the tablet available commercially.
The above study shows that the dosage form available in form of strip/thin film containing cetirizine dihydrochloride as active ingredient possess high degree of dissolution than the branded products. It is also demonstrated that the bitter taste of the dosage form is negligible.
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Following is the process adopted for the manufacture of the oral strip/thin film dosage form.
Cellulose paste including ingredients like hypromellose, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, pregelatinised starch or microcrystalline cellulose or a mixture thereof is prepared in a jacketed mixture and stored for the preparation. A solution of required strength containing cetirizine dihydrochloride as active ingredient is made either in water, acetone or alcohol or in a mixture of these solvents. The drug solution thus prepared is added to the cellulose paste prepared above with constant stirring for uniform distribution in the cellulose paste.
To the cellulose paste sweetness of required amount are added followed by plasticizer and titanium dioxide. Lastly flavours and approved colours are further added to impact flavour and colour to the strip/film.
The above-prepared slurry containing different components with their required quantity is carried out to the feed tank on the processing machine. Then the processing machine dispenses the slurry with extra and measured precision form formation of oral strip sheet. The formed strip is then passed on to the drier for drying of strip so formed. As drying is over these oral strips are then wound on the master reel. In the stage of dispensing of the slurry care is taken maintaining extra precision so that the strip/thin film so formed should be reality dissolvable dosage in the mouth.
The master reels are then loaded on the packaging machine and cut into individual sealed in aluminium pouches and heat-sealed. The packaging unit is perfectly synchronized with the dispenser where the strips are formed for better packing of the end product.
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Advantage of the invention:
1. This novel dosage form of cetirizine dihydrochloride is termed as mouth dissolving strip/film. This strip when placed on tongue dissolves in fast three minutes and gives effect within two minutes.
2. The fear of bitterness of drugs is avoided due to presence of higher concentration of sweetness in the strip.
3. Easy acceptability in children as before realization the medicines is administered.
4. Very easy to administer.
5. Gives a fast relief with accuracy of dosing.
6. The dosage forms are available in absence of disintegrating agents.
Complete stability studies for accelerated as well as long term shall be performed before launch of product in the market/regulatory purposes for marketing approval, etc.
These and other modifications and variations to the present invention may be practiced by those of ordinary skill in the art, without departing from the spirit and scope of the present invention, which is more particularly set forth in the appended claims. In addition, it should be understood that aspects and various embodiments may be interchanged both in whole or in part. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the invention so further described in such appended claims.
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WE CLAIM
1. A pharmaceutical oral dosage form containing cetirizine dihydrochloride of easy and rapid dissolution in the mouth comprising of cetirizine dihydrochloride as pharmaceutically active ingredient in an effective amount, cellulose as the base, sweeteners, plasticizers, flavours and colours and titanium dioxide characterised in that the flavoured sachet dosage form is a thin film or strip.
2. A pharmaceutical oral dosage form as claimed in claim 1, characterised in that the cellulose base are selected from hypromellose, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, pregelatinised starch or microcrystalline cellulose or a mixture thereof.
3. A pharmaceutical oral dosage form as claimed in claim 1, characterised in that the sweeteners are selected from maltodextrin, sucralose, sorbitol or mixture thereof.
4. A pharmaceutical oral dosage form as claimed in claim 1, characterised in that the plasticizers are selected from polyethylene glycol, propylene glycol, or mixture thereof.
5. A pharmaceutical oral dosage form as claimed in claim 1, characterised in that the titanium dioxide is added to dosage form to impart opacity to the thin film/strip.
6. A process for manufacturing a pharmaceutical dosage form as claimed in claim 1, comprising the steps of:
(i) preparing a solution with effective amount of cetirizine
dihydrochloride in a suitable solvent;
(ii) adding sweeteners, plastcizers, titanium dioxide, cellulose base
and flavours and colours of desired amount to the content of
step(i);
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(iii) carrying out the contents of step (ii) to the feed tank of the
processing machine;
(iv) dispensing the contents of the step (iii) with extra precision for
formation of oral strip/film by the dispensing apparatus;
(v) drying the completed oral strip through a dryer;
(vi) making wound of the dried oral strip/film on the master reel;
(vii) cutting the master reel into individual strips in the packing
machine and sealing in pouch.
7. A process for manufacturing a pharmaceutical oral dosage form containing
cetirizine dihydrochloride as claimed in claim 6 characterised in that the solvents for dissolution of the active ingredients are selected from water, acetone, alcohol or a mixture thereof.
8. A pharmaceutical oral dosage form containing cetirizine dihydrochloride in the form of thin film/strip as herein described with reference to the description.
9. A process for manufacturing the pharmaceutical dosage form containing cetirizine dihydrochloride as herein described with reference to the description.

Date: 03.04.2007
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ABSTRACT OF THE INVENTION
The present invention discloses a novel pharmaceutical oral dosage form of cetirizine dihydrochloride in form of thin strip/film. Other pharmaceutical adjuvants to improve the properties of the film/strip is disclosed including adding sweeteners and flavours to suppress the bitterness of cetirizine dihydrochloride. The very delicate dosage form requires special provision for manufacturing via specially designed apparatus and that is adopted in order to carry out the invention.
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