Form 2
The Patents Act, 1970
COMPLETE SPECIFICATION (Section 10)
NOVEL PHARMACEUTICAL DOSAGES FORM, IN
PARTICULAR, ORAL STRIP OR THIN FILM FORM OF ACTIVE
DOMPERIDONE 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 domperidone 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
Domperidone is an antidopaminergic drug with antiemetic properties that can either be used orally or intravenously, for suppressing nausea, vomiting and dyspepsia. The drug has also been used for stimulating lactation. It increases lower oesophagal sphincter pressure, antral and duodenal contractions, gastric emptying of liquids and semi solids, and shortens the stationary phase for solids in the stomach. Domperidone is chemically represented as l,3-dihydro-5-chloro-l-(l-(3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl)-4-piperidinyl)-2H-benzimidazol-2-one. Domperidone is generally available in tablet, liquid and suppository form. There have been a number of efforts in developing a dosage form of domperidone to meet the patient compliance.
UA 77907 relates to the pharmacy, in particular to the method for manufacturing the tablet dosage form of domperidone. The method comprises mixing domperidone, lactose, the starch, and polyvinyl pyrrolidone, wetting the mixture obtained with the starch paste followed by wet and dry granulation, the treatment of the granules with the powder of the stearate of the alkaline earth metal, and the compression. The invention allows one for making easier the manufacturing process used for producing the tablets intended for treating the functional disorders of the gastrointestinal tract with concurrent increase of the strength characteristics of the tablets without the coat providing for the immediate release of the active ingredient throughout the shelf life of the product.
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KR 950010149 discusses a process for preparing 5-chloro-l-[l-{3-(2,3-dihydro-2-oxo-1 H-benzimidazole-1 -y 1) propyl} -4-piperidy 1 -1,3 -dihydro-2H-benzimidazole-2-one] (domperidone liquid medicine) comprising the steps of (a) dissolving the domperidone with a hydrochloric acid, a sodium hydroxide, a citric acid and/or a phosphate salt as a pH regulating agent to be pH 2-6, (b) adding a honey, a fructose, a sorbitol, an aspartame, a glycerine and/or a beta-cyclodextrin as a sweetening agent, a paraoxy benzoic acid propyl (or methyl) and/or a sodium benzoate as an antiseptics, an ethanol as a soluble aid, a distilled water as a solvent, and an aromatic to the dissolved solution, and (c) mixing them. The domperidone is used for treating gastrointestinal disease.
CN 1449757 provides a domperiodone oral disitegrant tablet preparation. Its composition includes medicine active component, filling agent, corrective, disitegrant, lubricating agent and glidant. Its medicine active component includes dopamine receptor antagonist and gastroprokinetic, and its disitegrant agent is selected from cross-linked polyvinylpyrrolidone, carboxymethyl starch sodium and microcrystal cellulose or their mixture, and corrective is selected from aspartame. Said invention adopts direct addition of disitegrant in the prescription so as to attain the effect of quick disitegration. Its preparation process is simple, and it is convenient for taking in.
WO 2004084867/CN 1456148 relates to, the colon-targeted pharmaceutical compositions of gastrointestinal motility drugs and their use. The compositions consist of the colon-targeted materials and the unit dose that comprising clinical effective amount of gastrointestinal motility drugs and the pharmaceutical acceptable excipients. The said colon-targeted materials may be the outer coating surrounding the unit dose or capsules that can solve in the colon. CN 1528302 utilizes ultramicropulverization and dripping pill preparation production process to make domperiodine dripping pills, and can attain the goal of raising disintegration
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and dissolution speed, quickly obtaining therapeutic effect, raising stability of medicine, reducing dose of auxiliary material, reducing production cost and convenient administration. Said pill not only can be sucked, but also can be swallowed, and its compliance property is good.
The above-discussed prior arts address mostly a pharmaceutical formulation containing domperidone in tablet 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 domperidone. Patients are in need of a formulation containing domperidone that can deliver the medicinal value of domperidone 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 domperidone 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.
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
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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.
Each of these dosage forms has their drawbacks that limit their usefulness. A dosage form containing domperidone 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 three minutes, preferably less than about ninety seconds, more preferably in less than about thirty seconds and most preferably in less than about twenty or about fifteen seconds.
Taste is one of the most important parameters governing patient compliance. Undesirable taste is one of several important formulation problems that are encountered with certain drugs. Oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients. Several oral pharmaceuticals, numerous food and beverage products, and bulking agents have unpleasant, bitter tasting components. 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. Domperidone also taste very bitter if given sublingually. The conventional solution for masking of bitter drugs as discussed above 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
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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 domperidone 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 domperidone 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.
Our effort and research findings are of worth in this respect and we have formulated a pharmaceutical composition comprising domperidone as active ingredient in form of thin film or strip. The present invention takes care of these loopholes of the prior art discussed before and makes available of domperidone in form of thin film or strip at no longer patient compliance. The main theme of the invention is a pharmaceutical composition containing domperidone available in form of thin film or strips without addition of disintegrants and bitter taste masking properties to meet patient compliance.
OBJECTIVE OF THE INVENTION
The main objective of the invention is formation of a pharmaceutical dosage form containing effective amount of domperidone in the form of a thin film/strip.
Another objective of the invention is formation of the dosage form of domperidone to suppress its bitter taste and availing ease dissolution in the mouth.
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Further more objective of the invention is to achieve a pharmaceutical dosage form of domperidone that finds easy administration, very fast acting and easy acceptability in patients. .
One more objectibve of the present invention is to make a dosage form containing domperidone 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 domperidone 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 domperidone.
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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel pharmaceutical oral dosage form of domperidone 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. domperidone 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
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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. domperidone 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.
Domperidone 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 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
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strip/thin film, commercial grade inactive titanium dioxide is provided to the dosage form in required amount.
Since the strip/thin film which contains domperidone 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
domperidone 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 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
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domperidone 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 280 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 30, 60, 90, 120 seconds of incubation the thin film dosage form of the present invention containing domperidone released 30%, 50%, 70% 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 domperidone 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.
Table 1:

Invented product containing domperidone as drug of dosage 20 mg Tablet containing domperidone as a drug of dosage 20 mg available in brand names of immediate release type.
Time in seconds Release profile (%) Time in seconds Release profile (%)
0 NIL 0 NIL
30 30 30 2
60 50 60 10
90 70 90 20
120 82 120 35
150 90 150 50
180 100 180 65
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Table 2:

Invented product containing domperidone as drug of dosage 30 mg Tablet containing domperidone as a drug of dosage 30 mg available in brand names of immediate release type.
Time in seconds Release profile (%) Time in seconds Release profile (%)
0 NIL 0 NIL
30 28 30 2
60 49 60 9
90 67 90 18
120 80 120 32
150 90 150 48
180 100 180 63
Table 3:

Invented product containing domperidone as drug of dosage 40 mg Tablet containing domperidone as a drug of dosage 40 mg available in brand names of immediate release type.
Time in second Release profile (%) Time in second Release profile (%)
0 NIL 0 NIL
30 25 30 2
60 48 60 9
90 65 90 17
120 80 120 30
150 90 150 45
180 100 180 62
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"In vivo" trials have shown that the thin films/strips forms of the invention provide more rapid absorption than commercial formulations containing domnperidone. A group of patents were used as volunteers and time taken by them to reach the maximum blood level concentration of the drug taking 30 mg tablets available commercially and with a strip containing 30 mg domperidone 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 domperidone 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.
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 domperidone 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.
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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.
Advantage of the invention:
1. This novel dosage form of domperidone is termed as mouth dissolving strip/film. This strip when placed on tongue dissolves in fast three minutes and gives effect within one minute.
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.
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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 domperidone of easy and rapid dissolution in the mouth comprising of domperidone 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 domperidone 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);
(iii) carrying out the contents of step (ii) to the feed tank of the
processing machine;
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(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
domperidone 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 domperidone 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 domperidone 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 domperidone 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 domperidone. 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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