Form 2
The Patents Act, 1970
COMPLETE SPECIFICATION
(Section 10)
NOVEL PHARMACEUTICAL DOSAGES FORM, IN PARTICULAR,
ORAL STRIP OR THIN FILM FORM OF ACTIVE ALPRAZOLAM
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 alprazolam 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
Alprazolam chemically identified/named as 8-chloro-l-methyl-6-phenyl-4H-1,2,4-triazolo(4,3-a)( 1,4)benzodiazepine is a short-acting drug in the benzodiazepine class used to treat anxiety disorders and as an adjunctive treatment for depression. It is also used primarily for short-term relief of excessive anxiety, nervous tension, panic attacks and for certain phobias. There have been a number of attempts and also successes in making a pharmaceutical formulation containing alprazolam as active for easy administration of the said drug. 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.
Sustained-release alprazolam formulations have been investigated, including formulations wherein alprazolam is dispersed in a polymer matrix, for example a hydroxypropylmethylcellulose (HPMC) matrix. Franz et al. (1987), Journal of Controlled Release, 5, 159-172, examined effects of several formulation variables on in vitro alprazolam release rate from such a matrix formulation comprising HPMCs of different viscosity grades, sodium carboxymethylcellulose (sodium CMC) and lactose. US 2005163843 make disclosure of a sustained-release and controlled-release formulations containing

alprazolam. The dosage forms may have particular dissolution profiles and plasma concentrations. Preferred dosage forms do not contain hydroxypropyl methylcellulose. WO 2007010369 is directed towards the preparation of extended release Alprazolam formulation. The formulation thus obtained provides an efficient mode of delivery of Alprazolam in a continuous manner. WO 2005030180 discusses a sustained release dosage form of alprazolam via once-a-day a therapeutically effective average steady-state plasma alprazolam concentration, where the maximum attained plasma concentration is achieved more than about 14 hours after administration. The slow, sustained release reduces side effects such as sedation and abuse potential.
US 2004141923/WO 2005030167 makes disclosure of a buccal aerosol sprays or capsules using polar and non-polar solvents have now been developed which provide alprazolam for rapid absorption through the oral mucosa, resulting in fast onset of effect. US 2006233718 relates to aerosols containing alprazolam, estazolam, midazolam or triazolam that are used in inhalation therapy. WO 2004105767 describes the use of pharmaceutical compounds in pharmaceutical compositions for sublingual administration, including as active ingredient thereof, an agonist of the central receptor of benzodiazepinics chosen among diazepam, lorazepam, bromazepam, triazolam, alprazolam, flunitrazepam, nitrazepam and midazolam maleate, in a mixture with a pharmaceutical excipient consisting of, at least, 70% of the weight of the final formulation containing 40-45% by weight of lactose, 15-27% by weight of sorbitol and 12-16% by weight of cellulose. WO 0172338 discloses a pharmaceutical composition for transmucosal delivery contains an inclusion complex of alprazolam and a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin such as 2-hydroxypropyl beta-cyclodextrin, and a pharmaceutically acceptable carrier therefor. The pharmaceutical composition is of particular application in the treatment of Generalised Anxiety Disorder or for the management of panic disorders.
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US 2006147516 relates to taste masking system, taste masked formulations, dosage forms made from those formulations and methods of making those formulations that involve dissolving or dispersing a pH dependant polymer and alprazolam in a solvent, granulating using that material or forming layers over a solid support therewith. This can be followed with the use of an overcoating layer. DE 4428986 emphasizes a solid alprazolam formulations comprise: (i) a carrier comprising (a) 0-70 wt.% water-soluble alpha -, beta or psi -cyclodextrin, mono-, di-, oligo- or polysaccharide or polyvinylpyrrolidone (PVP) of average mol.wt. 25000-120000; (b) 0-10 wt.% water-insoluble hydrophilic porous or non-porous Si02, Ti02 or AI2O3; and/or (c) 0-10 wt.% non-ionic surfactant having an HLB value of 13-18; and (ii) 2-20 wt.% disintegrant comprising sodium starch glycolate, crosslinked PVP or sodium carboxymethyl cellulose.
The immediate-release alprazolam tablet formulation currently marketed as Xanax(R) tablets by Pharmacia Corporation can be prescribed for administration of up to four doses per day for treatment of anxiety and, in some instances, in excess of four doses per day for treatment of panic disorder. The said tablet taste bitter and takes more time for release of alprazolam.
The above-discussed prior arts address mostly a sustained release pharmaceutical composition containing alprazolam (as the said drug acts for a short time), different mode of delivery of alprazolam and effect of alprazolam on body. Though the immediate release form is disclosed it takes a little more time to act. Patients are in need of a formulation containing alprazolam that can deliver the medicinal value of alprazolam at a very faster rate without bitter taste. It is intended to increase the plasma concentration of alprazolam in blood in a short duration to get fast relief. Some times frequent and continuous administration of alprazolam is not advisable as it leads to other side effects. It is desired to take the
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dosage form at the time of need. None of the available technologies have covered the underlying problem.
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 of the times it is very much inconvenient to take oral dosage form of bitter taste due to bitterness of the drugs. Alprazolam also taste very bitter if given sublingually. Our effort and research findings are of worth in this respect and we have formulated a pharmaceutical composition comprising alprazolam 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 alprazolam at no longer patient compliance.
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 drug. This approach some time fails to deliver the drug immediately whenever required. Administration of such masked tablets especially becomes inconvenient in case of
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children who cannot easily swallow the tablet. Encountered with such shortcomings a novel dosage form containing alprazolam 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 alprazolam 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.
OBJECTIVE OF THE INVENTION
The main objective of the invention is formation of a pharmaceutical dosage form containing effective amount of alprazolam in the form of a thin film/strip.
Another objective of the invention is formation of the dosage form of alprazolam 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 alprazolam that finds easy administration, very fast acting and easy acceptability in patience.
One further more objective of the invention is to devise a process for manufacturing the dosage form containing alprazolam as active ingredient.
SUMMARY OF THE INVENTION
The present invention discloses a novel pharmaceutical oral dosage form of alprazolam in form of thin strip/film. Other pharmaceutical adjuvants to improve
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the properties of the film/strip is disclosed including adding sweeteners and flavours to suppress the bitterness of alprazolam.
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 alprazolam 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. alprazolam 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. alprazolam 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
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apparatus/machine of very high accuracy and precision is implemented during the process operated.
Alprazolam 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 strip/thin film, commercial grade inactive titanium dioxide is provided to the dosage form in required amount.
Since the strip/thin film which contains alprazolam 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.
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Following are the components in the dosage form in their respective proportions.

Thin film/strip Wt.% in the composition
alprazolam in the strip Pharmaceutically effective amount
Base material 20-75
Sweetness 25-45
Plasticizers 5-15
Titanium Dioxide 42-60
Flavours & colours Quantity desired for acceptability and best taste
In vitro dissolution profile/rate of the invented dosage form of alprazolam with respect to a branded immediate release tablet containing same active ingredient (i.e. alprazolam drug) is studied and the following results are realised.
Table 1:

Invented product containing alprazolam as drug of dosage 125 ug Tablet containing alprazolam as a drug of dosage 125 u,g available in brand names of immediate releasetype.
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
Ihr. — 1hr. 90
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Table 2:

Invented product containing alprazolam as drug of dosage 250 ug Tablet containing alprazolam as a drug of dosage 250 fig available in brand names of immediate release type.
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. 85
Table 3:

Invented product containing alprazolam as drug of dosage 500 ug Tablet containing alprazolam as a drug of dosage 500 ug available in brand names of immediate release type.
Time in min. Release profile(%) Time in min. Release profile (%)
1 50 1 NIL
2 60 2 2
5 85 5 15
12 100 12 25
20 — 20 50
45 — 45 70
1hr. — 1hr. 78
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The above study shows that the dosage form available in form of strip/thin film containing alprazolam 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 alprazolam 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
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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 alprazolam is termed as mouth dissolving strip/film. This strip when placed on tongue dissolves in fast 10 minutes 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. 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.
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CLAIM
1. A pharmaceutical oral dosage form containing alprazolam of easy and rapid dissolution in the mouth comprising of alprazolam 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 alprazolam 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 alprazolam as claimed in claim 6 characterise 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 alprazolam 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 alprazoalm as herein described with reference to the description.

Date: 26/03/07

Abstract Of The Invention

The preset invention discloses a novel pharmaceutical oral dosage form of alprazolam inform 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 alprazolam. 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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