Design and Characterization of Fast Dissolving Films of Cilnidipine Solid Dispersions

The major problem in formulation of oral films of cilnidipine is that it belongs to BCS Class II moiety. Pharmacologically Cilnidipine is a dihydropyridine (DHP) type of calcium channel antagonist. Unlike other calcium channel antagonists, Cilnidipine blocks the influx of Ca 2+ ions into both vascular smooth muscle at the level of L-type Ca 2+ channels and neuronal cells at the level of N-type Ca 2+ channels. Cilnidipine was absorbed over 2 hours and its bioavailability is 64-90%. Hence there is a need to increase the solubility and oral bioavailability of cilnidipine by formulating it in to solid dispersions and incorporating the same in to the formulation of fast dissolving films which gives fast onset of action. Nine formulations (FC 1 FC 9) of cilnidipine films were prepared and evaluated for their physical characteristics such as thickness, weight variation, folding endurance, drug content uniformity and gave satisfactory results. The compatibility of the drug in the formulation was confirmed by FTIR and DSC studies. The formulations were subjected to disintegration, in vitro drug release studies and formulation FC 6 was found to be best formulation which contain HPMC, PVP as film forming polymers along with cilnidipine solid dispersion with poly ethylene glycol at weight ratio of 1:4 showed excellent film forming characteristics such as disintegration time of 49.3 sec and percentage drug release 97.92 within 8 minutes.


INTRODUCTION
Recently fast dissolving drug delivery system have started gaining popularity and acceptance as new drug delivery systems which aim to enhance safety and efficacy of a drug moiety by formulating into a convenient dosage form for administration and to achieve better patient compliance. They undergo rapid disintegration in the salivary fluids of the oral cavity in less than a minute, where they release the drug 1 . Most of the drug is swallowed orally with the saliva and the absorption of drug takes place in the gastro-intestinal tract. The fast dissolving dosage forms are referred by various names by researchers like quick disintegrating, orally disintegrating, rapidly disintegrating, mouth dissolve or melt in mouth dosage forms 2 . Cilnidipine is calcium channel antagonist, which is used in the treatment of Hypertension. Cilnidipine belongs to class II drug in BCS classification the major problems with its low solubility in biological fluids, which results into poor bioavailability after oral administration and late onset of action. In order to enhance the solubility of cilnidipine and subsequently dissolution and absorption. Solid dispersions of cilnidipine were prepared by melting technique at different drug carrier (PEG 400) weight ratios and were evaluated 3 . The optimized formulation of solid dispersions, Cilnidipine : PEG 400 (1:4) was selected and used in the preparation of cilnidipine films by solvent casting method, which offers superiority over other.

Advantages of cilnidipine fast dissolving film include 4,5
 Patient of increases Hypertension not capable to swallow large quantities of water.
 In case of high blood pressure quick onset of action required because uncontrolled high blood pressure create Strokes, Heart attack, Kidney Problem.
 Hypertension markedly reduces functional ability and extremely restlessness in such cases rapid onset of action required.
 No Marketed cilnidipine film available in India.
 Specially intended to geriatric patients who have problem of swallowing.

Standard Curve of Cilnidipine
Cilnidipine is a yellow fine powder which was practically insoluble in water. Though several methods are reported for its estimation, the UV spectrophotometric method was employed in the ISSN: 2249-3387 www.ajptr.com 208 study. Cilnidipine shows maximum absorbance at 240 nm in simulated saliva pH 6.8. Based on this information, a standard graph was constructed ( Figure No.1).

Preparation of cilnidipine solid dispersion
Cilnidipine and PEG 400 are mixed using mortar and pestle. PEG 400 as carrier in different proportions 1:1, 1:2, 1:3 and 1:4 (drug:carrier) as shown in (Table No.2). To accomplish a homogenous dispersion the mixture is heated at or above the melting point of all the components with constant stirring. It is then cooled to acquire a congealed mass. It is crushed and sieved.

Percentage Practical Yield
Percentage practical yield is calculated to know about percent yield, thus its help in selection of appropriate method of production. Solid dispersions were collected and weighed to determine practical yield (PY) from the following equation ( Figure No The release profile of an entrapped drug predicts how a delivery system might function and gives valuable insight into its in vivo behaviour. In vitro release profile for each solid dispersion as well as pure drug was performed using USP type 2 dissolution apparatus. Sample equivalent to 5 mg of cilnidipine was added to 900ml of phosphate buffer of pH 6.8 at 37±0.5°C and stirred at 75 rpm (Table no.

Evaluation of fast dissolving films a) Physical appearance and surface texture of films:
This parameter was checked simply with visual inspection of films and evaluation of texture by feel or touch.

b) Weight uniformity of films:
Three films of the size 2×2 cm were weighed individually using digital balance and the average weights were calculated.

c) Thickness of films:
Thickness of the films was measured using screw gauge with a least count of 0.01mm at different spots of the films. The thickness was measured at three different spots of the films and average was taken.

d) Folding endurance of patches:
The flexibility of films can be measured quantitatively in terms of what is known as folding endurance. Folding endurance of the films was determined by repeatedly folding a small strip of the ISSN: 2249-3387 www.ajptr.com 210 films (approximately 2x2 cm) at the same place till it broke. The number of times films could be folded at the same place, without breaking gives the value of folding endurance.

e) Drug-polymer interaction study of films:
There is always a possibility of drug-excipients interaction in any formulation due to their intimate contact. The technique employed in this study to know drug-excipients interactions is IR spectroscopy. IR spectroscopy is one of the most powerful analytical techniques which offer the possibility of chemical identification. Infra-red spectra of pure drug cilnidipine and formulations were scanned by using FTIR and DSC, by a thin film method.

f) Drug content uniformity of films:
The films were tested for drug content uniformity by UV Spectrophotometric method. Films of 2×2 cm size were cut from three different places from the casted films. Each film was placed in 100 mL volumetric flask and dissolved in simulated saliva pH 6.8 and 2 mL is taken and diluted with water up to 10 mL. The absorbance of the solution was measured at λ max 240 nm using UV/ visible spectrophotometer (Shimadzu). The percentage drug content was determined.

g) In vitro drug release:
The release rate of cilnidipine fast dissolving oral films was determined by using USP dissolution testing apparatus II at 50 RPM. The film with 2×2 cm was placed in the 500 mL of 6.8 pH simulated saliva as dissolution medium, and temperature was maintained at 37°C. From this dissolution medium, 5 mL of the sample solution was withdrawn at different time intervals. The samples were filtered through Whitman filter paper and absorbance was determined 240 nm using double beam UV-Visible spectrophotometer.

h) Permeation study:
The They were found be physically flexible and dry. The folding endurance was measured manually, by folding the FDF repeatedly at a point till it broke. The breaking time was considered as the end point.
Folding endurance was found to be highest for FC 7 and lowest for FC 6. It was found that the folding endurance of the FDF was affected with increase of carrier concentration. The folding endurance values of the FDF were found to be optimum and therefore, the FDFs exhibited the good physical and mechanical properties. The folding endurance of films was found to be in the range of 321 to 364 (Table No. 5).As all the formulations contain different amount of polymers, the thickness was gradually increased with the amount of polymers. All the film formulations were found to have thickness in the range of 0.14 to 0.23 mm and were observed within the limits.

Weight variation
The randomly selected film strips about 2 × 2 cm areas were cut at different places from the casted film and weight was measured. Weight of film strip units varies from 43.36 to 55.33 mg. The results indicated that selected carriers used in method of solid dispersion preparation, proportion of carrier used have reduced the variation and improved the uniformity of the distribution in casted films (

Drug content
The prepared film formulations were studied for their drug content. The drug was dispersed in the range of 84 % to 98 %. Suggesting that drug was uniformly dispersed in all films.

In vitro dissolution studies
The in-vitro drug release profiles of the formulations in SSF pH 6.8 show differences depending on their composition. The rate of drug release from the HPMC E15 films was significantly lower than the films containing PVP K30 along with the HPMC E15 ( Figure No.10 and 11). This is due to the swelling of the high viscosity HPMC E15 upon contact with the dissolution medium, resulting in the formation of a thick matrix gel. The formulation FC6 films containing combination of HPMC E15 and PVP K30 as hydrophilic polymers shows high percentage of drug release (97.92%) within 8 minutes compared to that of films containing HPMC E15alone and PVA along with HPMC E15 as a polymers.    shows high percentage of drug release within 8 minutes compared to that of films containing HPMC alone as a polymer, combination of HPMC E15 and PVA. Present study reveals that fast dissolving films can be a potential novel drug delivery system for geriatric, pediatric and also for general population.