Form 2
The Patents Act, 1970
COMPLETE SPECIFICATION
(Section 10)
NOVEL PHARMACEUTICAL DOSAGES FORM, IN PARTICULAR, ORAL STRIP OR THIN FILM FORM OF ACTIVE DICLOFENAC SODIUM 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 diclofenac sodium of ease and rapid dissolution and of bitter taste masking in the form of strips or thin films and a process for its preparation.
BACKGROUND/PRIOR ART
Diclofenac belongs to a group of medicines called non-steroidal antiinflammatory drugs (NSAIDs). It works by blocking the action of a substance in the body called cyclo-oxygenase. Cyclo-oxygenase is involved in the production of various chemicals in the body, some of which are known as prostaglandins. Prostaglandins are produced in response to injury or certain diseases and would otherwise go on to cause pain, swelling and inflammation. Arthritic conditions are one example of such a diseases. Diclofenac is used to relieve pain and inflammation in a wide range of conditions, including arthritis, gout, sprains, fractures, back pain and following minor surgery. All the medicines in the NSAID group reduce inflammation caused by the body's own immune system and are effective painkillers. Diclofenac ([2 (2,6-Dichloranilino) - phenyl] - acetic acid) is mostly available in form of its sodium salt for ease adiministration in the body. However, all types of dosage forms available containing alprazolam can never meet every aspects of patient compliance. The present invention attempts to cover one important aspect, which is not available in the existing prior arts. An amicable and economically viable process has been adopted in the present invention to obtain the invented product, which is discussed in the specification.
2

Pharmaceutical formulation containing diclofenac sodium is available commercially in the form of gastric juice-resistant tablets or retardierter form for oral application in many pharmaceutical preparations in the trade. Diclofenac is characterised by a fast and reliable effect and relatively small frequency of side effects. Various types of techniques have been applied in the said field for preparation of a formulation containing diclofenac for its ease, rapid and effective administration in human.
US 5202159 discloses a preparation method of sodium diclofenac enteric-coated microcapsules by spray drying technique comprising the steps of (a) dissolving sodium diclofenac in an appropriate amount of distilled water; (b) adding an effective amount of excipients to the above solution to form a suspension; (c) adding methacrylic acid-ethyl acrylate copolymers (Eudragit L 30D) and polyethyleneglycol 6000 (PEG 6000) as the enteric-coating material to form a slurry; (d) atomizing the slurry to form spray-dried powder; (e) mixing the spray-dried powder with a mixture of microcrystalline cellulose (neocel) and pregelatinized starch (flo-starch); and (f) compressing the powder mixture into a microdispersed enteric tablet. The spray drying technique could be easily performed to prepare the enteric-coated microcapsules with aqueous latex polymer dispersion such as Eudragit L 30D as an enteric-coating polymer.
EP-A-0 365,480 discloses a tablet fast-disintegrating, which contains Diclofenac in a particle size from 4 to 100 urn and is not gastric juice-resistant covered. This invention uses the fact that Diclofenac is insoluble as acid in water and exhibits therefore not the very bad, bitter taste water-soluble Diclofenac sodium. Thus this tablet before the application is dispersable in water, and a demand of the Diclofenac therapie, i.e. the light application, is fulfilled thereby. The disadvantage of this invention is rated that Diclofenac is used as acid, which must be micronisiert as water-insoluble substance for the reaching of a sufficiently fast absorption. This is an expensive process step, which the costs of the
3

production in strong measure increase. Further the acid is wettable hydrophob and thus act with water, so that the tablet a tensid must contain.
Furthermore by DE-A-3 909,520 a solid, rapidly disintegrating dosage form in the form of effervescent tablets for producing an aqueous suspension of diclofenac for peroral administration contains diclofenac in micronised form provided with a permeable, swellable coating, together with pharmaceutical excipients. It contains Diclofenac with a content of citric acid and sodiumhydrogencarbonat, which disintegrate into water, whereby this time Diclofenac is set free in acid form of a particle size 200 |im and with a covering from Polyvinylpyrrolidon or an etherified cellulose in the aqueous medium.
DE-A-3 915,150 (example 1) describes a long-working Diclofenac sodium preparation, for which one processes a mixture from Diclofenac sodium and an acid, i.e. citric acid, to spherical granulates, which one sprayingcoats with measure retarding the active substance release.
With another execution form after DE-A-3 915,150 (example 2) that is used managing stated long-working granulates from Diclofenac sodium and acid than core, applied on the Diclofenac sodium for spherical granulates, which will provide again with a coating retarding the active substance release. The shortworking Diclofenac sodium portion of the finished preparation does not entalt an acid.
US 2006240104 discloses a formulation comprising: a co-polyester comprising (a) the reaction product of a polycondensation polyester and (b) glycolide; wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and ethylene glycol, and the co-polyester comprises about 40% by weight of the polycondensation polyester based on the total weight of the co-polyester; and a drug selected from the group consisting of indomethacin, diclofenac sodium, and ketoprofen.
4

US 4897270 discloses a pharmaceutical tablet which comprises a tablet core containing the antibiotic cefuroxime axetil and a film coat which serves to mask the bitter taste of the cefuroxime axetil upon oral administration. It has been found that conventional film-coated tablets reduce the bioavailability of cefuroxime axetil and the invention overcomes this by control of the film coat rupture time and use of a tablet core, which disintegrates immediately following rupture of the film coat.
US 2005079213 discloses a solid oral dosage composition of cefuroxime axetil comprising a tablet inside a capsule, the capsule serving to mask the bitter taste of the drug upon oral administration. This tablet-in-a-capsule format is bioequivalent to the commercial film-coated tablet.
The above discussed prior arts either disclose about the sustained/differential/modified release formulation containing diclofenac sodium or on the bitter taste masking skill of the said drug that taste bitter.
However, disadvantages exists, there
1. Diclofenac with the most frequently used preparations after the passage of the stomach is only set free and therefore partially only after substantial delay to be absorbed;
2. Diclofenac particularly in retardierter form with the primary liver passage by the liver is filtered from the blood and, without becoming
clinically effective, is metabolically eliminated.
In particular the gastric juice-resistant tablets can make large problems taken in the reliability of the entrance of the effect thereby that the duration of stopover from these covered tablets lies to sober gift within the range of 0 to 4 hours, with the meals however within the range of 7 to 16 hours, depending upon type of the meal. This is a principle-conditioned characteristic of gastric juice-resistant covered single proportioned medicine forms. It is connected with emptying
5

kinetics of stomach contents. For the treatment rheumatism tables of the illnesses it is however essential to receive reproducible results with very fast effect entrance. Here it concerns gastric juice-resistant covered pellets, which set their active substance free after leaving the stomach fast, in mixture with gastric juice-resistant covered Retard pellets, which make a slow release possible after leaving the stomach. The pellets must be emptied only from the stomach, which can take on the average about 1 hour, before they release their active substance. A rheumatism patient with pain would like to feel however very fast after income of his medicine an effect. A deceleration time of approximately 1 hour is often not acceptable thereby.
The kind of the production of these gastric juice-resistant Retardpellets is very complicated, and the patient must take a relatively large hard gelatin capsule, which can lead particularly with older rheumatism patients, in particular with swallowing difficulties, to large problems, so that this medication cannot be appliziert by many patients.
An improvement of the medicine form, which carries all therapeutic aspects of the rheumatism treatment with oral Diclofenac sodium, would be a gastric juice-resistant not covered, stomach-compatible tablet, which can be swallowed or be dispersed with patients with swallowing difficulties before the application in water and drunk in such a way.
It is the need of the hour to make an approach for an ease and rapid dissolution formulation of diclofenac sodium for immediate relief from pain by rapid absorption in the body.
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
6

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. Most of the times it is very much inconvenient to take oral dosage form of bitter taste due to bitterness of the drugs.
In order to overcome these sorts of problems while taking oral formulations containing bitter drugs, conventional approach of masking the tablet is generally adopted. A number of prior arts use to discuss such technical problems and find solution to this effect.
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 diclofenac sodium 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 diclofenac sodium 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
7

immediately. For attaining such dosage form, a very specific manufacturing process employing a specially designed apparatus is utilised.
OBJECTIVE OF THE INVENTION
The main objective of the invention is formation of a pharmaceutical dosage form containing effective amount of diclofenac sodium in the form of a thin film/strip.
Another objective of the invention is formation of the dosage form of diclofenac sodium 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 diclofenac sodium that finds easy administration, very fast acting and easy acceptability even in children.
One further more objective of the invention is to devise a process for manufacturing the dosage form containing diclofenac sodium as active ingredient.
SUMMARY OF THE INVENTION
The present invention discloses a novel pharmaceutical oral dosage form of diclofenac sodium 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 diclofenac sodium.
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 diclofenac sodium for easy and rapid dissolution and of bitter taste masking in the
8

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. diclofenac sodium utilised for the 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. diclofenac sodium 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.
Diclofenac sodium 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,
9

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 diclofenac sodium 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
Diclofenac sodium in the strip Pharmaceutical^ effective amount
Base material 10-75
Sweetness 15-35
Plasticizers 5-15
Titanium Dioxide 42-60
Flavours & colours Quantity desired for acceptable and best taste
In vitro dissolution profile/rate of the invented dosage form of diclofenac sodium with respect to a branded tablet containing same active ingredient (i.e. diclofenac sodium drug) is studied and the following results are realised.
10

Table 1:

Invented product containing diclofenac sodium as drug of dosage 125 mg Tablet containing diclofenac sodium as a drug of dosage 125 mg available in brand names.
Time in min. Release profile(%) Time in min. Release profile (%)
1 50 1 NIL
2 75 2 2
5 100 5 15
10 — 10 25
20 — 20 50
45 ~ 45 70
1hr. — 1hr. 90
Table 2:

Invented product containing diclofenac sodium as drug of dosage 250 mg Tablet containing diclofenac sodium as a drug of dosage 250 mg available in brand names.
Time in min. Release profile(%) Time in min. Release profile (%)
1 50 1 NIL
2 60 2 2
5 85 5 15
10 100 10 25
20 — 20 50
45 — 45 70'
1hr. — 1hr. 90
11

The above study shows that the dosage form available in form of strip/thin film containing diclofenac sodium 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 and even children take it easily if prescribed.
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 diclofenac sodium 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
12

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 diclofenac sodium is termed as mouth dissolving strip/film. This strip when placed on tongue dissolves in fast 10 seconds and gives effect within five minutes.
2. The fear of bitterness of drugs is avoided due to presence of higher concentration of sweetness in the strip.
3. Very easy to administer
4. Easy acceptability in children as before realization the medicines is administered
5. Gives a fast relief with accuracy of dosing.
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.
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its scope.
13

WE CLAIM
1. A pharmaceutical oral dosage form containing diclofenac sodium of easy and rapid dissolution in the mouth comprising of diclofenac sodium 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 of the active ingredient 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;
14

(iv) dispensing the contents of the step (in) 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 diclofenac sodium 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 diclofenac sodium 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 diclofenac sodium as herein described with reference to the description.

Date:26/03/07
15

Abstract Of The Invention
The present invention discloses a novel pharmaceutical oral dosage form of diclofenac sodium 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 diclofenac sodium. 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.
16