INTRODUCTION

1. INTRODUCTIONEpilepsy is a neurological disorder which is characterized by repeated seizures and known to

affects people of all age group. The word epilepsy is originated from Greek word epilepsia

means seizures. Seizures are electrical impulses discharged by nerve cells present in the

brain. Possible reasons of seizures are head injuries, abnormal brain development, genetic

and infectious illness (meningitis). The drugs used for the treatment of epileptic seizures are

known as antiepileptic drugs which are known to decrease the frequency or severity of

seizures. Most of the antiepileptic drugs act by any of these three mechanisms; modulation of

voltage gated ion channels, enhancement of gamma amino butyric acid (GABA) mediated in-

hibitory neurotransmission or by glutamate mediated excitatory neurotransmission. Approxi-

mately 20–30% of patients with epilepsy have seizures that are resistant to treatment given

with the most of antiepileptic drugs available in the market which is responsible for break-

through seizures in patients. It is found that most of the seizures are resolved by its own with

or without any specific treatment but a seizure that remains for more than 5 min. then it re-

quire immediate medical intervention. In addition, there are certain emergency conditions

where administration of medications for long term is required but due to poor access to oral

route and difficulties such as associated pain with intravenous formulations of medications,

alternative routes of drug administration are required. One factor that should be considered

while treating epileptic patient is whether patients can swallow the medication they need, and

it has been found that majority of patients report swallowing difficulty, under these circum-

stances fast dissolving intra oral dosage forms offer an option for epileptic patient. Therefore,

both acute and chronic epileptic attacks require administration of medications using multiple

types of formulations [1].

1.1. Oral administration1.1.1. Gastrointestinal absorption

Absorption is defined as the amount of drug that leaves the site of administration and the ex-

tent to which it reaches into systemic circulation. The extent of drug absorption is dependent

on numbers of factors such as anatomy and physiology of the gastrointestinal (GI) tract, the

physiochemical properties of the drug such as drug particle size, molecular weight, partition

coefficient, extent of ionization etc, and the type of dosage form. Most of the drugs molecules

depending upon their chemical properties are absorbed either by passive diffusion or active

transport mechanism in the GI tract. In passive diffusion process the drug moves from the

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INTRODUCTION

area of high concentration to the area of lower concentration. In this process the rate of ab-

sorption is proportional to the drug concentration gradient across the barrier. The active trans-

port mechanism is energy dependent process which is generated through hydrolysis of ATP.

There are some other drugs which are absorbed by a combination of both passive and active

mechanism where the transporting proteins can increase or decrease the rate of absorption de-

pending on their location and direction in which they transport the drug or substrate molecule

across the cell membrane. For example L-amino transporters are influx transporters which fa-

cilitate the oral absorption of gabapentin by active transport mechanism [2]. Increasing the

dose of gabapentin leads to saturation of the L-amino transporter which results in decreased

absorption of gabapentin [3]. Drug absorption involves number of steps; firstly it is required

to administer via some route of administration such oral, topical, parenteral in some specific

dosage form such as tablets, capsules, solution or suspension. Absorption via different route

is a primary focus in drug development process because drug must be absorbed before any

pharmacological effect can take place. The absorption of some drugs is affected by some of

the non favorable conditions existing in gastro intestinal tract like presence of digestive en-

zymes of gastrointestinal lumen and epithelium, poor absorption efflux, and hepatic first pass

metabolism, drugs given by the oral route of administration are absorbed from the GI tract

reach the liver through the hepatic portal vein before entering the systemic circulation. Be-

fore reaching the systemic circulation there is every possibility of drug to undergo first pass

metabolism in the GI tract and in the liver, resulting in a decreased drug bioavailability. For

example both midazolam and stiripentol known to have low bioavailability due to extensive

first pass metabolism [4]. Presystemic metabolism and/or low GI absorption of a drug in-

crease the possibility of high inter subject variation in terms of dose and concentration. Thus

to minimize the problem of poor drug absorption through gastrointestinal tract recent studies

are focused on developing intraoral drug delivery systems [5]. Various routes of administra-

tion such as inhalation, transdermal, parenteral have made tremendous progress as a drug de-

livery system, but even than oral route has been the most favorable route of administration.

oral cavity as a structural organ perform various functions but its function as a site for the

oral absorption of drugs was noted as early as 1847 by Sobrero who discovered the absorp-

tion of nitroglycerine via oral mucosa. Oral transmucosal drug delivery system offers high

patient acceptance and compliance. Apart from patient compliance, oral mucosa is robust and

less viable to irritation or any damage as it is routinely exposed to various foreign com-

pounds. Oral mucosa is highly per fused with blood vessel and has high blood flow. Thera-

peutic serum concentration of a drug can be achieved rapidly as oral mucosal blood vessels

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INTRODUCTION

are close to the surface and also have well developed lymphatic drainage. The delivery of

drugs within in the oral cavity can be studied under two headings: (i) local delivery directly to

the focused area and (ii) systemic delivery through the buccal or sublingual route of adminis-

tration. Various sites for the local drug delivery in the oral cavity are: tongue, gum, pharynx,

larynx, adenoids and tonsils. Intra oral drug delivery via oral cavity is classified into three

classes: i) sublingual delivery means systemic drug delivery through the mucosal membrane

lining the floor of mouth. ii) buccal delivery mean drug delivery through buccal mucosa

which consist of lining the cheeks , gums and the back of upper and lower lips. ii) Local de-

livery means drug delivery through periodontal, odontal and gingival for the treatment of bac-

terial and fungal infections and ulcer of oral cavity [6].

1.1.2 Overview of oral mucosa

The oral mucosa can be separated into two areas, the outer vestibule area which is bounded

by lips and cheeks and the oral cavity. The oral cavity consists of the floor of mouth, base of

tongue, hard palate, soft palate, tonsils and pillars of fauces. The oral cavity is situated within

the dental arches framed on the top by the hard and soft palates and on the bottom by the

tongue and floor of the mouth. Schematic representation of different linings oral mucosa is

given in Fig. 1.1. The oral cavity is lined by a mucosal membrane called as the oral mucosa

which is divided as buccal, masticatory, alveolar, lining, labial and specialized mucosa. 60%

of the oral mucosal surface area is formed by the buccal, sublingual and the mucosal tissues

at the ventral surface of the tongue. The oral epithelial consist of stratified squamous

epithelial [7].The outermost layer of oral mucosa is known as stratified epithelium, below this

layer lies a basement membrane and below this a lamina propria and the sub mucosa as

shown in Fig. 1.2. The oral mucosa also contains sensory receptors such as the taste receptors of

the tongue and receptors that initiate swallowing which are present in the post part of the oral

cavity and upper part of pharynx.

The oral mucosa is anatomically divided into

a) Epithelium

b) Basement membrane and Connective tissues

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INTRODUCTION

Figure 1.1: Schematic representation of the different linings of oral mucosa

Figure 1.2: Structure of oral mucosa

a) Epithelium

The thickness of the oral epithelium measures about 100 cm2. [8] The function of oral

epithelium is to protect the underlying tissue against harmful agents in the oral environment

and also from fluid loss. [9] The oral epithelium is partly keratinized and its thickness varies

considerably between sites. The average thickness of various regions of the human oral

mucosa epithelium is given in Table 1.1

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INTRODUCTION

Table 1.1: Average thicknesses of various regions of oral mucosa

Region Average epithelial thickness (µm)

Skin (mammary region) 100-200

Hard palate 250

Attached gingival 200

Buccal mucosa 500-600

Floor of mouth 100-200

b) Basement Membrane and Connective Tissue The basement membrane (BM) is a continuous layer of extracellular materials and forms a

boundary between the basal layer of epithelium and the connective tissues of the lamina pro-

pria and sub mucosa. It provides barrier to the passage of cells and some large molecules

across the mucosa. Below the basement membrane lies the lamina propria, a continuous sheet

of connective tissue consists of a collagen fiber network and cellular components in a hy-

drated ground substance. The organization of network determines mechanical stability, resis-

tance to deformation, and extendibility of the tissue. The basement membrane is also supplied

with blood capillaries and nerve fibers that serve the mucosa. [10]

1.1.3 Secretion of saliva

The surface of the mucosal membrane is constantly washed by approximately 0.5 to 2.0 L of

saliva daily produced by salivary glands. The secretion of saliva is carried out by three pairs

of major salivary glands, namely the parotid, the sub maxillary, and the sublingual glands.

Minor salivary glands that are situated in the buccal palatal and retro molar region of the oral

cavity have little contribution in saliva secretion. The presence of saliva in the mouth is im-

portant because of the two main reasons:

a) Permeation of drug across moist membrane occurs much more readily than across non

moist membrane; compared to drug absorption across the GI tract and skin.

b) Drugs are commonly administered orally in a solid form. The drug must therefore first

disintegrate and dissolve in the saliva before its absorption through the oral mucosa;

means the drug cannot be absorbed directly from a solid tablet.

1.1.4. Absorption via buccal mucosa

The absorption of drug through the oral mucosa by passive transport mechanism follows two

permeation pathways: Para cellular and Tran cellular pathway. A drug can also follows these

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INTRODUCTION

two routes simultaneously, but at one time one route is usually preferred over the other de-

pending on the physicochemical properties of the drug molecule. Usually a lipophilic com-

pound would show low solubility in this environment because of hydrophilic nature of intra-

cellular spaces and cytoplasm. However a hydrophilic compound will have difficulty in per-

meating cell membrane due to lipophilic nature of cell membrane. Therefore, for a lipophilic

compound the intercellular spaces are the major barrier and for a hydrophilic compound the

cell membrane acts as the major transport. Since the oral epithelium consists of a series of

layers of cells called as laminated epithelium a solute permeation may involve a combination

of para cellular and trans cellular pathway. The route that is preferred, however, is generally

the one that pose the least amount of hindrance to passage of drug molecule. [11] Fig. 1.3

represents the different routes of drug permeation.

Figure 1.3: Schematic representation of different routes of drug permeation

1.2. Intraoral drug delivery systemIntraoral (within the oral cavity ) drug delivery through the mucosal lining of the oral cavity

provides an alternative route of delivering drugs that cannot be given orally due to their ex-

tensive first pass metabolism, traditionally such drugs are given by parenteral route of admin-

istration but again this route is not preferred due to poor patient compliance. To achieve opti-

mal drug therapy one must ensure that the patient receive the correct medication, at the right

dosage form and at the most convenient dosing interval. For this not only the pharmacody-

namic and pharmacokinetic properties of the drug, but also patient compliance need to be

considered. One of the major factors determining the patient compliance is the use of non-in-

vasive drug delivery system. As the cost of developing new drug molecule is too high, the re-

search is being done on the development of new dosage forms of the existing drug molecules,

this approach provided an opportunity for the utilization of intra oral drug delivery system.

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INTRODUCTION

Intra oral drug delivery system can be used to achieve three basic objective firstly for the de-

livery of the drugs that cannot be given by the conventional oral route of administration, sec-

ondly for the enhancement of pharmacokinetic and pharmacodynamic performance of the

drugs, thirdly for the improvement of the patient convenience and/or compliance, e.g. orally

disintegrating tablets (ODT) or films (ODF), for patients with difficulty in swallowing con-

ventional tablets. The drugs intended to be absorbed through oral mucosa are formulated ei-

ther as extended release or as immediate release. Intra oral drug delivery systems can there-

fore be used to achieve either of these strategies. Those intended for extended release are

mostly buccal adhesive drug delivery systems which remain in buccal cavity for longer dura-

tion of time. Drug delivery systems intended for immediate release into oral cavity are pri-

marily fast disintegrating and fluid drug delivery systems (tablets, films, and lozenges). In

this case the objective can either be fast dissolution or quick absorption through the oral mu-

cosa, mainly to avoid pre-systemic metabolism of the drug or for complete disintegration be-

fore swallowing for quick therapeutic action. [12]

1.2.1. Fast Dissolving Tablets

Fast disintegrating tablets are those which when placed on the tongue disintegrate with in

fraction of seconds to release the drug which disperse or dissolve in the saliva. The concept

of Fast dissolving tablets are also known as mouth dissolving tablets, melt-in mouth tablets,

repimelt tablets, or dispersible tablets, porous tablets etc. first came in the late 1970s as an al-

ternate option for conventional tablets to patients having swallowing difficulty.[13]

1.2.1.1. Features of fast dissolving drug delivery systems [14]

Useful for the patients who find swallowing difficulty, such as, stroke victims, bed ridden

patients, patients with renal failure and those who are reluctant to swallow tablets such as

small children’s, old age and psychiatric patients.

Fast onset of action resulting in enhanced bioavailability.

Provide pregastric absorption of drugs from mouth, pharynx and esophagus as saliva

passes down, there by avoid hepatic first pass metabolism.

Convenient for administration where no water is available.

Good mouth feels which helps to change the feeling in which medication is regarded as

bitter pill.

The risk of choking or suffocation during oral administration of conventional dosage form

such as tablet, capsules is avoided, thus providing improved safety.

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INTRODUCTION

Provide good stability, accurate dosing, easy manufacturing, small packaging size and

easier handling by patients.

Offers properties of liquid dosage form in the form of solid dosage form.

Offers new business option like product differentiation, extended patent life cycle.

1.2.1.2. Disadvantage of fast dissolving tablets

1. Have low hardness and fragile in nature.

2. Hygroscopic in nature required to be stored in dry place.

3. Leave grittiness in mouth if not formulated properly.

4. Not compatible with anti cholinergic drugs and with Sjogren’s syndrome or dryness of

mouth where there is insufficient production of saliva.

5. Requires special packaging for the proper storage and stabilization of product.

1.2.1.3. Selection of drugs

The ideal features of a drug candidate to be selected for an FDT include

Should have good taste, not bitter taste.

Should have low dose i.e. less than 20mg.

Small to moderate molecular weight.

Should have good stability in water and saliva.

Should exist in partially non ionized form at the oral cavity pH.

Should have log p value more than 1, or preferably more than 2.

Ability to show good permeability across oral mucosal tissue.

Unsuitable drug characteristic for ODT

Drugs having short half-life requiring frequent dosing.

Drugs having bitter or unacceptable taste because taste masking cannot be achieved.

Drugs requiring controlled or sustained release.

1.2.1.4. Formulation techniques of fast dissolving tablets

Different techniques used for the formulation of fast dissolving tablets are classified as con-

ventional and patented techniques. Fig. 1.4 enlists the various conventional and patented ap-

proaches.

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INTRODUCTION

Conventional Patented

1. Freeze drying 1. Zydus technology 2. Sublimation 2. Orasolv technol-ogy 3. Spray drying 3 Durasolv technology

4. Moulding 4. Wowtab technology 5. Mass extrusion 5. Flashdose tech-nology 6. Direct compression 6. Flashtab technol-ogy 7. Cotton-candy process 7. Oraquick tech-nology 8. Nanonization 8. Pharmabust technol-ogy 9. Fast dissolving films 9. Nanocrystal technology 10. Melt granulation 10. Frosta technology

Figure 1.4: Enlists the various conventional and patented approaches

Freeze drying or lyophilization

Freeze drying also known as lyophilization, in this process water is re-moved by freezing and then sublimating at a low temperature under re-duced pressure to get dried form which has amorphous appearance that offer more rapid dissolution of the formulation than other available solid products. The tablets formulated by this technique offers highly porous open matrix network into which saliva rapidly penetrate to disintegrate lyophilized mass into individual particles when placed over the tongue.

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Techniques

INTRODUCTION

Apart from the matrix forming agent and active constituents, the final composition of lyophilized tablets may contain other excipients, which im-prove the formulation characteristics. These additives include suspending agents, wetting agents, preservatives, stabilizers, coloring agents and fla-vors. The drug characteristics desired for freeze drying formulations are: lipophilicity, small dose, chemically inert, stable, small particle size and tasteless.

Advantage

Suitable for heat sensitive drug candidates as process is carried out low temperature. [15]

Disadvantage

i) High processing cost of product due expensive lyophilization equip-ment.

ii) Long lyophilization cycle therefore time consuming manufacturing process.

iii) Highly porous and fragile product that make the handling and use of conventional packing difficult.

iv) Poor product stability during storage under stress.

Sublimation

This process involves the use of some inert volatile material as sublimating agent like urea,

urethane, naphthalene, camphor, thymol and ammonium bicarbonate etc to other tablet excip-

ients to prepare formulation blend. During the process of drying the added volatile material is

sublimed with the formation of porous structure on the surface of powder particles. The pre-

pared powder blend after evaluation for pre compression parameters is then compressed into

tablets. Other solvents like cyclohexane, benzene, organic acids like adipic acid, and lower

fatty acids such as palmitic acid and capric acid etc can also be used as volatile and pore

forming materials. Fast dissolving tablets having high porosity and good mechanical strength

can be formulated by this method.

Spray drying

In this technique a particulate support matrix is formed for the preparation of fast dissolving

tablets by conventional spray drying technique. In this method an aqueous composition of

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INTRODUCTION

support matrix containing polypeptides and other components such as bulking agent, volatile

material to form fine, porous powder are mixed with active ingredient and compressed into

tablets. The formulations composition consist of polypeptides hydrolyzed and nonhy-

drolyzed gelatin as a supporting agent for the matrix formation, mannitol as a bulking agent,

ethanol as volatilizing agent and sodium starch glycolate/ croscarmellose as a disintegrant.

The fast dissolving tablets prepared by this technique known to disintegrate within 20 sec-

onds. Disintegration and dissolution can be accelerated by adding minimum amount of an ef-

fervescent producing agent (e.g. citric acid and sodium bicarbonate).

Molding

Molded tablets are formulated by using water soluble ingredients. The active constituents

along with other excipients are moistened using solvents like ethanol or water. The moistened

powder blend is then pressed into mold plates to form wet mass and compressed into tablets

under pressure lower than that is used for the compression of conventional tablet. The solvent

present can be removed by conventional air drying technique. Tablets prepared by molding

method are less compact than conventional tablets.

Advantage

(i) Molded tablets posses porous structure, which facilitates rapid disintegration and disso-

lution.

(ii) Molded tablets offer good taste due to the presence of water-soluble sugars such as

mannitol in dispersion matrix.

Disadvantage

Molded tablets are fragile and have poor mechanical strength due to which there is a greater

chance of breakage or erosion during normal handling and opening of blister packs. Mechani-

cal strength can be increased by adding sucrose, acacia or polyvinyl pyrrolidone.

Mass extrusion

In this technique, a mixture of active drug and other excipients is mixed using solvent mix-

ture of water soluble polyethylene glycol, and methanol to prepare soft compact mass and

then the softened mass is pushed through a die of the required cross-section through the ex-

truder or syringe to produce a cylindrical shaped granules, which are finally shaped and sized

uniformly with the help of heated blades to get tablets. The dried cylindrical granules can be

coated to mask the taste of bitter tasting drugs. [16]

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INTRODUCTION

Direct compression method/ disintegrant addition method

In direct compression method, tablets are compressed directly from the mixture of the drug and commonly available excipients along with super-disintegrants in the concentration range of 2-5% using conventional tablet punching machine. The mixture to be compressed must have good flow properties and compressibility under pressure thus making pretreatment and wet granulation unnecessary, thus there are only few drugs candi-dates that can be directly compressible into tablets of desired quality. A type of disintegrant and its concentration are of prime importance in tablet disintegration and dissolution. The other factors to be considered for fast tablet disintegration are particle size distribution, wetting time, tablet porosity, hardness and water absorption capacity. Direct compres-sion method also known as the disintegrate addition method and is eco-nomical that is easy to implement over industrial scale. [17] Ideal require-

ments, advantages and limitations of direct compression method are given in Table 1.2. Steps

involved in the direct compression method are given in Fig. 1.5.

Table 1.2: Ideal requirements, advantages and limitations of direct compression technique

S. No Ideal requirements Advantages Limitations1. Flow ability Cost effective production Segregation2. Compressibility High dose can be added. Variation in functionality3. Dilution potential Faster dissolution Low dilution potential4. Rework ability Less wear and tear of punches Rework ability5. Stability Simple validation

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Drug + other excipients

Superdisintegrants croscarmellose sodium, crospovidone, sodium starch glycolate

Mixing all ingredients

Compression

INTRODUCTION

Figure 1.5: Schematic representation of the direct compression process for preparation of FDTs

Cotton-candy process

In this process spinning mechanism is utilized to from floss like crystalline structure which is

very similar to cotton candy therefore named as cotton candy process. The technology is used

for the preparation of a matrix using mixture of drug and polysaccharides such as sucrose,

dextrose, lactose and fructose by simultaneous application of floss melting (180-266 °F) and

spinning known as FLOSS. The fibrous nature of the floss is similar to the cotton-candy

fibers. Polysaccharides such as polymaltodextrins and polydextrose can be converted into

fibers at 30-40% lower temperature range that is used for sucrose. Due to this alternate option

various heat sensitive drugs can be safely processed using this technique. This process pro-

vide a highly porous product having very pleasant mouth feel due to fast solubilization of

sugars in presence of saliva. [18]

Nanonization

In this process, the particles of the drug are reduced to nano size range by milling the drug

through wet milling process. The agglomeration of particles can be prevented by surface ad-

sorption of the nano crystals on selected stabilizer. These are then compressed into a tablet.

This technique is very useful for less water soluble drugs. The bioavailability of the drug is

increased as the disintegration time is reduced to a significant extent leading fast dissolution

rate and absorption. Other advantages of this method are: cost effective, economical, wide

range of dose and conventional packing can be used. [19]

1.2.2. Fast dissolving films

Fast dissolving film or strip can be defined as a dosage form that uses a water dissolving

polymer which allows the dosage form to quickly hydrated by saliva, adhere to mucosa, and

disintegrate within a few seconds, dissolve and releases medication for oral mucosal absorp-

tion when placed on the tongue or oral cavity. Since sublingual mucosa is highly permeable

due to thin membrane and large veins therefore it gives rapid absorption and fast bioavailabil-

ity of drugs due to high blood flow.

1.2.2.1. Classification of oral film

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FDT

INTRODUCTION

Fast dissolving films are classified into three different types:

1) Oral flash release.

2) Mucoadhesive fast dissolving wafer.

3) Sustained-released mucoadhesive wafers.

1.2.2.2. Advantages of fast dissolving films

Fast dissolving films have some special advantages over other oral formulations such as-

Fast disintegration and dissolution within the oral cavity because of availability of larger

surface area which improves the onset of action, lower the dosing, and enhance efficacy

and safety profile of the medicament.

Most fast dissolving tablets are fragile and brittle in nature and need special package for

protection during storage and transportation. But the films are flexible, they are not as

fragile as ODTs, easy to transport, handle and storage.

Dose Precision is maintained by every strip.

Alternative to traditional products such as liquids, tablets, and capsules. Fast dissolving

films offer fast, accurate dosing in a safe and efficacious form.

Fast dissolving strips are suitable dosage forms for drugs that undergoes fast pass metabo-

lism.

1.2.2.3. Disadvantages of fast dissolving films

High doses cannot be in corporate.

Dose uniformity and thickness is a technical challenge.

1.2.2.4. Applications of fast dissolving films

Various applications of fast dissolving films as a drug delivery system are as follows

Topical applications

Fast dissolving films can be used for topical applications of agents such as antimicrobial

agents, analgesics for wound care and other applications.

Gastro retentive dosage forms

Dissolvable films can be used for the delivery of aqueous-soluble and poorly aqueous soluble

molecules of different molecular weights. Dissolution of the films could be facilitated by the

pH or enzyme present in the gastrointestinal tract, and could be used to treat gastrointestinal

disorders. [20]

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INTRODUCTION

1.2.2.5. Composition of fast dissolving films

The standard composition of a fast dissolving film is given in Table 1.1which consists of ac-

tive pharmaceutical ingredient, a water soluble film forming polymer (45%w/w), plasticizer

(0-20% w/w), surfactant, sweetener, saliva stimulating agent, filler, color and flavoring agent.

List of various natural and synthetic film forming polymers used in the preparation of fast

dissolving films is given in Table 1.3

Table 1.3: A typical composition of fast dissolving film

S.NO

Ingredients Amount

1 Active pharmaceutical agent 5- 30% w/w2 Film former 45% w/w3 Plasticizer 0-20% w/w4 Surfactant 2-6 % w/w5 Saliva stimulating agent q.s6 Sweetening 3-6 % w/w7 Flavor, color and filler q.s

Table 1.4: list of polymers used in the preparation of fast dissolving films

S. No Natural polymers Synthetic polymers1 Pullulan Hydroxypropylmethyl cellulose2 Gelatin Polyvinyl alcohol3 Pectin Polyvinyl pyrrolidone4 Sodium alginate Carboxy methyl cellulose5 Maltodextrin Polyethylene oxide6 Polymerized rosin Hydroxyethylcellulose7 Lycoat NG 73 Hydroxypropylcellulose8 Xanthan Kollicoat

1.2.2.6. Methods of preparation of fast dissolving films

Different methods used for the preparation of fast dissolving films are

1. Solvent casting method

2. Semisolid casting

3. Hot melt extrusion

4. Solid dispersion extrusion

5. Rolling method.

Solvent casting method

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INTRODUCTION

In this method the water-soluble polymer is dissolved in small quantity of water to form a

clear viscous solution. The API and other additives are solubilised in required amounts to get

the clear solution. This clear solution is then added to the aqueous viscous solution with con-

tinuous stirring. The entrapped air bubbles are removed by vacuum. The resulting solution is

cast as a film on plastic petri plate and allowed to dry, which is then gently removed from the

petri plate and cut into pieces of the required size. [21] Various steps involved in the prepa-

ration fast dissolving films using solvent casting method are shown in Fig. 1.6.

Figure 1.6: Steps involved in solvent casting method for the preparation of fast dissolving filmsSemisolid casting

The semisolid casting method involves the preparation of a solution of water soluble film

forming polymer. The prepared solution is then mixed to acid insoluble polymeric solution

which is prepared in ammonium or sodium hydroxide. Various acid in soluble polymers used

are cellulose acetate phthalate, cellulose acetate butyrate. Then optimum amount of plasti-

cizer is added to prepare a gel mass. Finally the gel mass is converted in to the films or rib -

bons by placing over heat controlled drums. The thickness of the film or ribbons prepared by

this method ranges from 0.015-0.05 inches. The acid insoluble polymer and film forming

polymer should be mixed in the ratio of 1:4. [22]

Hot melt extrusion

In hot melt extrusion process the drug carrier mixture is filled in the hopper and is conveyed,

mixed, and melted by the extruder. The die then shapes the melted mass in the required film

form. Hot melt extrusion has got numbers of advantages such as: lower degree of temperature

and shorter processing time of the drug carrier mixture (<2 minutes), absence of organic sol-

vents, continuous operation, minimum product wastage, good control of operating parame-

ters, and possibility to scale up.

Solid dispersion extrusion

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Water soluble ingredients are dissolved in water and API and other agents are dissolved in suitable solvent

to form a clear viscous solution.

Both the solutions are mixed.

Resulting solution is casted as a film in petridish and allowed to dry (60° C)

Polymeric film

INTRODUCTION

Solid dispersions are prepared by using specific carrier material and drug by solvent evaporation or kneading method and the formed solid dispersions are casted in to films by means of dies.

Rolling method

A suspension of drug is prepared in water or mixture of water and alcohol along with plasticizer. The prepared suspension is then shaped into film of specific thickness by rolling over roller and finally dried. [23]

1.2.3. Difference between fast dissolving films and tablets

Table 1.5 gives the difference between fast dissolving tablets and film formulations.

Table 1.5: Difference between fast dissolving films and fast dissolving tablets

Fast dissolving films Fast dissolving tabletsIt is available as thin film. It is available as small tablet.Fast rate dissolution due to large surface area.

Slower rate dissolution due to less surface area.

Greater flexibility than fast disintegrating tablets.

Less flexible and fragile as compared with oral films.

More compliance to patient. Less compliance to patient.Low dose can only be loaded. High dose can be loaded.There is no risk of choking. It has fear of chocking.

1.2.4. Marketed preparations of fast dissolving tablets and films

Some of the fast dissolving (tablets and films) products available in the market are listed in

Table 1.6and Table 1.7 respectively. [24]

Table 1.6: List of fast dissolving tablets available in the Indian market

Trade name Active drug ManufacturerUgesic Piroxicam Mayer organic Ltd.

Torrox MT Rofecoxcib Torrent PharmaEsulide MD Nimesulide Doff Biotech

Vomidon MD Domperidone Olcare labKazoldil MD Nimesulide Kaizen drugs

Zofer MD Ondenosteron Sun PharmaMosid MD Mosapride Torrent Pharma

Valus Veldecoxcib Glen markOlanex instab Olanzapine Ranbaxy

Romilast Montelukast Ranbaxy

Table 1.7: List of fast dissolving films available in the Indian market

Trade name Active drug Manufacturer

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INTRODUCTION

Listerine Cool mint PfizerBenadryl Diphenhydramine HCL PfizerSuppress Menthol Inno Zen,Inc.

Klonopin wafers Clonazepam Solvay PharmaceuticalsTheraflu Dextromethorphan NovartisOragel Menthol/Pectin DelGas-X Simethicone Novartis

Chloraseptic Benzocain PrestigeSudafed PE Phenylepinephrine Wolter Kulwer Health

careTriaminic Diphenhydramine Novartis

1.3. Design of Experiment1.3.1. Factorial design [25]

Factorial designs are used in experiments where the effects of different factors, or conditions,

on experimental results are to elucidate. Some practical examples of factorial designs are

such as to determine the effect of compression pressure and lubricant on the hardness of a

tablet formulation, or to determine the effect of disintegrant and lubricant concentration on

tablet dissolution or to determine the efficacy of a combination of two active ingredients in an

over the counter cough preparation. Factorial designs are the designs of choice for simultane-

ous determination of the effects of several factors and their interactions. Optimization of a

formulation or process is finding the best possible composition or operating conditions, De-

termining such a composition or set of conditions is an enormous task, probably impossible,

certainly unnecessary, and in practice, optimization may be consider as the search for a result

that is satisfactory and at the same time the best possible within a limited field of search.

1.3.1.1. Factors

A factor is an assigned variable such as concentration, temperature, lubricating agent, drug

treatment or diet. The choice of factors to be included in an experiment depends on experi-

mental objectives and is predetermined by the experiment. A factor may be quantitative or

qualitative. A quantitative factor has a numerical value assigned to it. For example, the factor

concentration may be given the value 1%, 2% and 3%.Some examples of qualitative factors

are treatments, diets, batches of materials, laboratories, analysts and tablet diluents. Qualita-

tive factors are assigned names rather than numbers.

1.3.1.2. Levels

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The levels of factors are the values or disintegration assigned to the factors. Examples of lev-

els are 30° and 50° for the factors temperature, 0.1 molar and 0.3 molar for the factor concen-

tration, and drug and placebo for the factors drug treatments. The runs or trials that comprise

factorial experiments consist of all combinations of all levels of the factors.

1.3.1.3. Effects

The effect of a factor is the change in response caused by varying the level (s) of the factor.

The main effect is the effect of a factor averaged over all levels of the other factors.

1.3.1.4. Interaction

Interaction may be thought of as lack of additivity of factor effects.

1.3.2. Advantages of factorial designs

In the absence of interaction, factorial designs have maximum efficiency in estimating

main effects.

If interaction exist, factorial designs are necessary to reveal and identify the interactions.

Since factor effect is measured over varying levels of other factors, conclusions apply to a

wide range of conditions.

Maximum use is made of the data since all main effects and interactions are calculated

from all of the data.

Factorial design is orthogonal; all estimated effects and interactions are independent of

other factors, Independence means that when we estimate a main effect.

1.3.3. Methods for optimization

There are four primary methods

1. Statistically designed experiments

2. Direct optimization method

3. One factor at a time

4. Non-systemic approach

Statistically designed experiments

The Statistically designed experiments are performed at one time to estimate the coefficients

of a model that predicts the responses within limits of the formulation or operating condi-

tions. This is generally the most powerful method, provided the experimentation zone has

been correctly identified and a mathematical model is used to map the response. The mathe-

matical model is capable of predicting the main effects, identifying significant variables, and

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INTRODUCTION

predicting the interactions. The response surface can be visual representation of the relation-

ship between measured responses and independent variables. This is a robust process and for-

mulation optimization by using a response surface methodology is an advantage of this ex-

periment.

Direct optimization method

In direct optimization method, the best is sequential simplex, is a rapid and powerful method

for determining an experimental domain.

One factor at a time:

In this method, variable is changed one-by-one to obtain the desired response, the one factor

at a time method is useful for a single response but not useful for multiple response.

Non-systemic approach:

In this method, the knowledge and intuition of the developer allow improving results, chang-

ing a number of factors at the same time is often surprisingly successful in the hands of

skilled workers.

1.3.4.32 Full factorial design [26]

A two factor three level (32) factorial design was used to optimize the formulation.

This design was constructed to determine the effect of the independent variables X1 and

X2 on the dependent variables.

Each factor was tested at three levels designated as -1, 0 and 1.The levels of the two fac-

tors were selected on the basis of preliminary experiments carried out before constructing

the factorial design.

All other formulations and manufacturing variables were kept constant throughout the

study. The software Design Expert was used for generating the experimental design,

molding the response surface and calculating the statistical evaluation.

The general model Eq. (1.1) was generated to fit the various data.

Y=Co+C1 X1+C2X2+C12X1 X2+C11 X12+C22 X2

2 (1.1)

Where Y= output/response

X1=Amount of independent variable 1

X2=Amount of independent variable 2

C0, C1, C2, C12, C11, C22 represent the regression coefficient of independent variable(X1

and X2).

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INTRODUCTION

The main effects (X1 and X2) represent the average result of changing one factor at a time

from its low to high value. The interception term (X1 and X2) shows the changes in re-

sponse when two factors were simultaneously changed. The polynomial terms (X12 and

X22) were included to investigate non-linearity.

1.3.5. Industrial applications of factorial design [27]

To find out which variable has got more influence on response so that it can be varied ac-

cordingly to produce a quality product.

To further improve the existing manufacturing technology.

To optimize the blend of disintegrants or excipients to achieve optimized formulation.

To select and develop proper packaging material and system for improved product stabil-

ity.

To study interaction among various factors and to screen and evaluate factors those influ-

ence the response.

To develop optimized formulation with minimum numbers of experimentation.

To investigate economically the cause-and-effect relationship in a given experimental set

up.

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