Formulation & development of fast dissolving film of Resperidone

Risperidone, an Antipsychotic drugs. Risperidone undergoes first pass metabolism on oral administration resulting in reduced bioavailability (60%). Thus the objective of the present study was to formulate and evaluate Fast Dissolving Film of Risperidone to overcome the limitation of bioavailability and increase patient’s compliance. In the present study Fast Dissolving Film were prepared by solvent-casting method using hydrophilic polymer HPMC K4M and PEG 400 as plasticizer. The eighteen formulations were prepared by the application of heat drying technique and evaluated for the fast dissolving films specification and characteristics. It was found that, the films has potential to modify drug release rate and possess good stability and less fragile property. The F9 batch of dried Fast Dissolving Film has shown promising drug release within 10 min (95.11%) and tensile strength


Introduction
Oral routes of drug administration have wide acceptance up to 50-60% of total dosage forms.Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance.The most popular solid dosage forms are being tablets and capsules; one important drawback of this dosage forms for some patients, is the difficulty to swallow.Drinking water plays an important role in the swallowing of oral dosage forms.Often people experience inconvenience in swallowing conventional dosage forms such as tablet when water is not available, in the case of the motion sickness (kinetosis) and sudden episodes of coughing during the common cold, allergic condition and bronchitis.For these reason, films that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention.Fast dissolving films are also called as sublingual films, melt in mouth films, Orodispersible films, rapid melts, porous films, quick dissolving etc. Fast dissolving films are those when put under tongue disintegrate instantaneously releasing the drug which dissolve or disperses in the saliva.The faster the drug into solution, quicker the absorption and onset of clinical effect (1).

Mechanism of Sublingual Absorption
The main mechanism for the absorption of the drug into oral mucosa is via passive diffusion into the lipoidal membrane.The absorption of the drug through the sublingual route is 3 to 10 times greater than oral route.For these formulation small volume of saliva is sufficient for disintegrate the whole formulation.In strategies of permeability, the sublingual area of oral cavity is more permeable than buccal (cheek) area.The difference in permeability is based upon relative thickness, blood supply, and degree of keratinization of these membranes.In addition to this, the difference in permeability is also based upon physicochemical properties of drug (3).
The absorption potential of the oral mucosa is influenced by the lipid solubility and therefore the permeability of the solution (osmosis), the ionization (pH), and the molecular weight of the substances.The absorption is transfer of the drug from its site of administration into systemic circulation, so it can be said that absorption is directly proportional to layer thickness.The extent of drug absorption follows, sublingual >buccal>gingival>palatal.Due to high permeability and rich blood supply, the sublingual route can produce rapid onset of action so the drug with short delivery period can be delivered and dose regimen is frequent (2).

 Absorption by Osmosis Process  Salivary Gland
The salivary glands consist of lobules of cells which secrete saliva through the salivary ducts into the mouth.The three pairs of salivary glands are parotid, submandibular and sublingual, which lies on the floor of the mouth.The acidic taste leads to the stimulation of salivary output, serving to avoid potential harm to acid sensitive tooth enamel by bathing the mouth in copious neutralizing fluids (4).
The sublingual artery travels forward to the sublingual gland, it supplies the gland and branches to the neighbouring muscles and to the mucous membranes of the mouth, tongue and gums.Two symmetrical branches travel behind the jawbone under the tongue to meet and join at its tip.Another branch meets and anastomoses with the submental branches of the facial artery.The sublingual artery stems from the lingual artery the body's main blood supply to the tongue and the floor of the mouth which arises from the external carotid artery.The proximity with the internal carotid artery allows fast access to its route supplying the greater part of the cerebral hemisphere (5,7).

Material
Risperidone was obtained as gift sample from by TOCRIS a biotechne brand R&D Cipla, Vikroli(Mumbai 400083), India.The HPMC K4M was purchased from TITEN BIOTECH LTD.Bhiwandi-301 019, Rajasthan, India.PEG400 was purchased from Oxford Laboratory, Mumbai, India.Ethanol was received from RESEARCH-LAB FINE CHEM INDUSTRIES, Mumbai 400 002 (INDIA).All other materials used were of analytical grade.

Compatibility Studies
A compatibility study for Risperidone was carried out with potential formulation excipients.PEG 400, HPMC K4M, complex.These samples were subjected to compatibility studies and stored for 30 days at elevated temperature and humidity conditions of 40 ± 2 0 C / 75 ± 5 % RH.

After 30days
 IR spectra of these stored samples was obtained. The assay of drug was performed using U.V. Spectrophotometer.

Formulation of Fast Dissolving Film of Risperidone
The composition of Risperidone Fast Dissolving films is given in Table  After complete drying of film, film was removed with the help of cutter.Wrap the film with aluminium foil and store in normal room temperature (6).
Figure 1 Fast Dissolving Sublingual Film Image of Batch F9

Thickness
As all the formulations contain different amount of polymers, hence the thickness was gradually increases with the amount of polymers (9).All the film formulations were found to have thickness in the range of 0.05mm to 0.15 mm.Result were shown in table 3.

Weight Variation
Three films each of 4 cm 2 were cut at three different places from the casted film and weight variation was determined.Weight variation varies from 49 mg to 66mg.Surface pH.The surface pH of the films was ranging from 6.67 to 6.93.Since the surface pH of the films was found to be around the neutral pH, there will not be any kind of irritation to the mucosal lining of the oral cavity.In Final optimized batch, 3%, 3.6% and 4.2% HPMC K4M concentration were tried using different proportion blend of ethanol and water mixture.Result concluded that all formulation having all desirable film characteristics.All formulations were giving 90% drug dissolution within 10 minutes (10).

Disintegration Time
It was observed that disintegration time varies from 19 to 30 sec for all the formulations.Disintegration time of Fast Dissolving Film containing HPMC K4M as polymer was affected by the thickness of the film.Disintegration time of the films was found to increase with increase in the amount of the polymer.Result were shown in table 4.

Folding Endurance
Folding endurance of film was increase with increase in the concentration of polymer.The number of time the film fold until it broke is reported.All the formulation contain different amount of polymers, hence the folding endurance gradually increase with the amount of polymers.The maximum folding endurance was occurred in F9 & F12 Batch.Result were shown in table 4.

Tensile Strength
The tensile strength was found to increase with increase with concentration of HPMC K4M.Formulation F9 was found maximum 53.95 mg.Result were shown in table 5.

Elongation
The percentage elongation of all the batches ranges from 5-20 mm elongation.It increased upon polymer as shown by the formulations.Formulation F9, F12 had highest percentage elongation.Result were shown in table 5.

Drug Content
The prepared film formulations were assayed for drug content.It was observed that all the formulations were satisfactory showing drug content as per labeled amount.Result were shown in table 5.

Dissolution Study
In-vitro drug release profiles of the formulations in pH 7.

Infrared Spectroscopy
Drug-excipients interaction study shown no interaction between Risperidone and selected polymers as there was no significant shift of peaks in IR spectrum.
Thus the Risperidone was found to be compatible with the selected excipients.

Color and Odour
Risperidone was observed and found to be white in color and odorless.

Identification by Melting point
The melting point of Risperidone was taken in triplicate and mean value was found to be 169-171ºC.

Solubility
Practically insoluble in water; sparingly soluble in alcohol; freely soluble in dichloromethane and dilute acid solutions.

Thickness
As all the formulations contain different amount of polymers, hence the thickness was gradually increases with the amount of polymers.All the film formulations were found to have thickness in the range of 0.05mm to 0.15 mm.Result were shown in table 3.

Weight Variation
Three films each of 4 cm2 were cut at three different places from the casted film and weight variation was determined.Weight variation varies from 49 mg to 66mg.Surface pH.The surface pH of the films was ranging from 6.67 to 6.93.Since the surface pH of the films was found to be around the neutral pH, there will not be any kind of irritation to the mucosal lining of the oral cavity.In Final optimized batch, 3%, 3.6% and 4.2% HPMC K4M concentration were tried using different proportion blend of ethanol and water mixture.Result concluded that all formulation having all desirable film characteristics.All formulations were giving 90% drug dissolution within 10 minutes.However, with economic aspect of formulation HPMC K4M with lower concentration and lower amount of ethanol preferable for optimized batch.
Result were shown in table 3.

Disintegration Time
It was observed that disintegration time varies from 19 to 30 sec for all the formulations.Disintegration time of Fast Dissolving Film containing HPMC K4M as polymer was affected by the thickness of the film.Disintegration time of the films was found to increase with increase in the amount of the polymer.Result were shown in table 4.

Folding Endurance
Folding endurance of film was increase with increase in the concentration of polymer.The number of time the film fold until it broke is reported.All the formulation contain different amount of polymers, hence the folding endurance gradually increase with the amount of polymers.The maximum folding endurance was occurred in F9 & F12 Batch.Result were shown in table 4. The tensile strength was found to increase with increase with concentration of HPMC K4M.Formulation F9 was found maximum 53.95 mg.Result were shown in table 5.

Elongation
The percentage elongation of all the batches ranges from 5-20 mm elongation.It increased upon polymer as shown by the formulations.Formulation F9 F12 had highest percentage elongation.Result were shown in table 5.

Drug Content
The prepared film formulations were assayed for drug content.It was observed that all the formulations were satisfactory showing drug content as per labeled amount.Result were shown in table 5.

Conclusion
Risperidone is used in the treatment of psychiatric disorder, mania and schizophrenia.Quick onset of action is desirable in acute treatment of these disorders.Oral delivery of Risperidone having many problems like poor bioavailability, extreme first pass hepatic metabolism, alteration of drug effect by various in vivo factors and poor patient compliance.So, fast dissolving sublingual film is promising approach for this drug candidate.
The fast dissolving sublingual film of Risperidone was prepared by the solvent casting method using HPMC K4M and PEG-400 as plasticizers.The prepared film was evaluated for different parameters and the results was found to be promising ensuring safe, and effective dosage form, which can be reproduced with a robust manufacturing process.
From the results obtained by this study it can be concluded that Risperidone given in form of fast dissolving sublingual film should be advantageous for patients suffering from psychosis, providing better patient compliance and effective mode of treatment in a disguised manner.From the present investigation, it can be conclude that fast dissolving sublingual film formulation can be a potential novel drug dosage form for paediatric, geriatric and also for general population.

1 .
Preparation of Fast Dissolving Film Weight accurate amount of polymer and socked in respective solvents for overnight.Risperidone was dissolved in required quantity of solvent.Mix the solution and add PEG 400 as a plasticizer.Heat the solution and keep standing for half an hour to get the proper viscosity.(Stir the solution continuously while heating).Sonicate the solution for 15 mins to remove the air bubbles.Then keep the solution overnight and next day casting procedure was carried out.Next day, lubricate the Petridish with help of castor oil.Pour the solution in Petridish and keep it overnight for proper drying.

Table 1
Composition of Risperidone Fast Dissolving Films

Table 2
Composition of Risperidone Fast Dissolving Films 2 artificial saliva show differences depending on their composition as given in table1 & 2. A rapid dissolution of all the film preparations was observed by the dissolution test, in which approximately 90% of Risperidone within 10 min.The formulations F1 to F18 showed approximately 95 to 99% drug release within 10 minutes.It was also observed that HPMC K4M & Pectin was able to modulate the Risperidone release as lower amount of HPMC K4M as well as Pectin resulted in release of drug a faster rate.Result were shown in table6 & 7.

Table 3
Evaluation Parameter of Sublingual Film Batch F1 to F18

Table 4
Evaluation Parameter of Sublingual Film Batch F1 to F18

Table 5
Evaluation Parameter of Sublingual Film Batch F1 to F18In-vitro drug release profiles of the formulations in pH 7.2 artificial saliva show differences depending on their composition as given in table.A rapid dissolution of all the film preparations was observed by the dissolution test, in which approximately 90% of Risperidone within 10 min.The formulations F1 to F18 showed approximately 95 to 99% drug release within 10 minutes.It was also observed that HPMC K4M & Pectin was able to modulate the Risperidone release as lower amount of HPMC K4M as well as Pectin resulted in release of drug a faster rate.Result were shown in table6 & 7.
Figure 2 In-vitro Dissolution Profile of Formulation Batch F1 to F18