Form 2
The Patents Act, 1970
COMPLETE SPECIFICATION
(Section 10)
NOVEL PHARMACEUTICAL DOSAGES FORM, IN PARTICULAR,
ORAL STRIP OR THIN FILM FORM OF ACTIVE
DIPHENHYDRAMINE HYDROCHLORIDE 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 diphenhydramine hydrochloride 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
Diphenhydramine hydrochloride, is an antihistamine drug having the chemical name 2-(Diphenylmethoxy)-N,N-dimethylethylamine hydrochloride and has the empirical formula C17H21NOHCI. It occurs as a white, crystalline powder and is freely soluble in water and alcohol and has a molecular weight of 291.82. There have been attempts to prepare a pharmaceutical composition containing diphenhydramine hydrochloride wherein the dosage forms appears in form of tablets, Capsules, syrup, pellets, gelcaps, lotions, ointments, aerosols etc. The oral dosage forms containing diphenhydramine hydrochloride are marketed/available mainly in form of tablets, Capsules, syrup, pellets and gelcaps. These different formulations are meant to serve different types of compliances the patient need and are of slow release, rapid release and disintegrated type. Various prior arts available to the applicant, stating about the oral formulation containing diphenhydramine hydrochloride and process for the said formulation is as follows.
NZ502264/EP102018 describes a process for the preparation of pellets containing a pharmaceutical active ingredient (i.e, diphenhydramine hydrochloride) and the process involves aqueous granulation of the mixture containing the active ingredient, extrusion, rounding and drying of the moist granules. The mixture used contains at least 50 wt.% of one active ingredient having solubility in water of 0.5 g/ml, the remaining percentage made up of a
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combination of microcrystalline cellulose and low-substituted hydroxypropyl cellulose. The pellets may also be enclosed in capsules or molded to form tablets, and may have a coating that provides controlled release or resistance to gastric
juices.
EP0661047 discloses a composition comprising 0.25-2.0% diphenhydramine hydrochloride or base; 0.1-10.0% colloidal oat extract; 0.05%-10% calamine or zinc oxide; 1-20% talc, 0.1-10% emulsifying agent; and, optionally, one or more ingredients selected among viscosity modifying agents, consistency regulators, water-repellent protectors, preservatives, emollients, antioxidants, chelating agents, lipidic substances and biocompatible polymers and find application in topical treatment of allergic type dermatosis accompanied by itching and/or pain.
US5635208 makes use of a granulation process for preparing a solid dosage form containing acetaminophen and diphenhydramine hydrochloride, as active agents. In addition, the solid dosage form produced by the process is described.
JP5000971 discloses a medicine composition for oral administration, effective for reducing influence of drinking too much alcohol, containing an antihistamine, especially 20-100mg of diphenhydramine hydrochloride as an active ingredient. The composition is suitable for oral administration form such as capsule, tablet or syrup and alleviates the symptom called hangover after drinking too much alcohol such as headache, feel like vomiting, tremble and ache of hand and foot.
Controlled release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise preparations with a prolonged, a sustained, a slow, a continuous, a retarded or an extended
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release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms.
Tablets and pills are well known. They are generally the preferred vehicles for oral administration of both prescription and over the counter medications. There are certain situations, however, in which the use of tablets 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 all of the medicament via deliberate or accidental rejection. An ideal alternative would be a solid dosage form that can be administered orally, which rapidly disperses in the mouth, 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. There have been prior attempts to make stable and quick dispersing dosage forms. Effervescent dosage forms and quick release coatings of insoluble microparticles are described in U.S. Patents Nos. 5,578,322 and 5,607,697. Freeze dried foams and liquids are described in U.S. Patents Nos. 4,642,903 and 5,631,023. Melt spinning of dosage forms is described in U.S. Patent Nos. 4, 5,380,473 and 5,518,730. Each of these dosage forms has their drawbacks that limit their usefulness. A dosage form containing diphenhydramine hydrochloride 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 five minutes, preferably less than about ninety seconds, more
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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. Diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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.
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Administration of such masked tablets especially becomes inconvenient in case of children who cannot easily sallow the tablet. Encountered with such shortcomings a novel dosage form containing diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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 diphenhydramine hydrochloride in the form of a thin film/strip.
Another objective of the invention is formation of the dosage form of diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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 as active ingredient.
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SUMMARY OF THE INVENTION
The present invention discloses a novel pharmaceutical oral dosage form of diphenhydramine hydrochloride 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 diphenhydramine hydrochloride.
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 diphenhydramine hydrochloride 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. diphenhydramine hydrochloride 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. diphenhydramine hydrochloride 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.
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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.
Diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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
diphenhydramine hydrochloride in the strip Pharmaceutically 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
In vitro dissolution profile/rate of the invented dosage form of diphenhydramine hydrochloride with respect to a branded immediate release tablet containing same active ingredient (i.e. diphenhydramine hydrochloride drug) is studied and the following results are realised.
Table 1:

Invented product containing diphenhydramine hydrochloride as drug of dosage 25 mg Tablet containing diphenhydramine hydrochloride as a drug of dosage 25mg available in brand names of immediate release type.
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
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Table 2:

Invented product containing diphenhydramine hydrochloride as drug of dosage 50 mg Tablet containing diphenhydramine hydrochloride as a drug of dosage 50 mg 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 diphenhydramine hydrochloride as drug of dosage 100 mg Tablet containing diphenhydramine hydrochloride as a drug of dosage 100 mg 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
15 100 15 25
20 ~ 20 50
45 ~ 45 70
1hr. — 1hr. 78
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A group of patents were used as volunteers and time taken by them to reach the maximum blood level concentration of the drug taking 100 mg tablets available commercially and with a strip containing 100 mg diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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
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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 diphenhydramine hydrochloride 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. 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.
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.
It should be apparent to those of ordinary skill from the descriptions provided that other embodiments of the invention can be contemplated that are not specifically disclosed herein but which nonetheless conform to the scope and spirit of the present invention. Thus, the present invention should not be construed as being limited in any way by the specific embodiments provided herein, which invention is limited solely by the claims that follow.
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WE CLAIM
1. A pharmaceutical oral dosage form containing diphenhydramine hydrochloride of easy and rapid dissolution in the mouth comprising of diphenhydramine hydrochloride 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 diphenhydramine
hydrochloride 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
diphenhydramine hydrochloride 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 diphenhydramine hydrochloride 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 diphenhydramine hydrochloride as herein described with reference to the description.

Date: 26/03/07
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Abstract Of The Invention
The present invention discloses a novel pharmaceutical oral dosage form of diphenhydramine hydrochloride 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 diphenhydramine hydrochloride. 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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