INTRODUCTION:

Many pharmaceutical dosages are administered in the form of pills, granules, powders, and liquids. The pills, which include tablets and capsules, are able to retain their shapes under moderate pressure. However, some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms due to fear of choking. Hence orally dissolving tablets have come into existence. Even with these differences, most of the existing oral dissolving drug delivery systems are in the form of solid tablets and designed to dissolve/disintegrate in the patient's mouth without the need to drink or chew. However, the fear of taking solid tablets and the risk of choking for certain patient populations still exist despite their short disintegration/dissolution times. Hence oral film drug delivery is a better alternative in such cases.

The delivery system consists of a very thin oral strip, which is simply placed on the patient’s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application.

It then rapidly disintegrates and dissolves to release the medication for oro-mucosal absorption or with formula modifications, will maintain the quick-dissolving aspects allow for gastrointestinal absorption to be achieved when swallowed¹. Various works on formulation and evaluation of fast dissolving oral films with different drugs have been carried out^2-6. No work has been carried out using perindopril for the formulation of fast dissolving oral films till now.

Fig:1 Sublingual Route of Administration

MATERIALS AND METHOD:

Perindopril obtained as Gift sample from Sun Pharmaceutical Ltd, Mumbai; HPMC, Chitosan and PEG procured from LOBA CHEME, Mumbai Sucrose obtained from Qualigens, Mumbai; Methanol procured from SDFCL, Mumbai

Method of preparation of Fast Dissolving Oral Film⁷:

Drug containing fast dissolving films were fabricated by the solvent casting method. The optimized amount of polymer was dissolved in 5ml of water and stirr continuously for 1 hour using magnetic stirrer. Optimized amount of sweetener, and Plasticizer were dissolved in 95% ethanol and then added to the polymeric solution. Then the optimized amount of drug was dissolved in 2ml of water and kept on sonication for proper dispersion. The drug solution was then added to the polymeric solution and stirred for 30 min using magnetic stirrer and was kept in undisturbed condition till the entrapped air bubbles were removed. The above solution was then casted on glass plate and was dried at controlled room temperature (25° - 30°C, 45 %RH) as well as at increased temperature (microwave oven). The film took approximately 48 hr to dry at controlled room temperature. The dried film was then carefully removed from the glass plate and was cut into size required for testing².

Procedure for construction of standard curve:

Standard stock solution of perindopril was prepared by dissolving 10 mg of drug in 10 ml of water to get concentration of 1000µg/ml. 1 m1 of standard stock solution of perindopril was then diluted to 10ml with water to get working standard solution of 100µg/ml. From the resultant solution 2, 4, 6, 8, 10µg/ml were prepared by diluting 0.2, 0.4, 0.6, 0.8, 1.0 to 10 ml with water. The absorbance was measured at 210nm using distilled water as blank and plotted to get the calibration curve.

EVALUATION OF THE PREPARED FILM ^8-11

Film Thickness:

As the thickness of film is directly concern with drug content uniformity so it is necessary to ascertain uniformity in the thickness of the film. It can be measured by micrometer screw gauge or calibrated digital Vernier Calipers at different strategic locations. The thickness of each of 10 film of each type of formulation was measured and the average was determined.

Weight Variation:

The mass of the films was determined by using analytical balance. When manufacturing the oral films, the film solutions were cast into sheets and then cut into smaller strips of 4 cm² (2cm×2 cm). Oral films were cut from different sheets and the variability between the respective polymers as well as the variability between the polymers were investigated. The individual weight each of 10 samples of each formulation was determined.

Hydration Study (water uptake/ swelling study) :

The film sample was weighed and placed on a preweighed stainless steel wire mesh. The wire mesh was then submerged in a petridish containing 20 ml distilled water. Increase in weight of the film was determined at regular time intervals until a constant weight was obtained. The hydration ratio of the film was calculated using following formula

Hydration ratio=

Where

Wt = weight of film at time t and

W0 = weight of film at zero time

Moisture Loss (Moisture Vapor Transmission) :

The percent moisture loss was determined by placing prepared film in desiccators containing anhydrous calcium chloride. After three days, the film was taken and reweighed. The percent moisture loss was calculated using following formula

Moisture loss =

Where

W₀ = initial weight

W_t = final weight.

Measurement of Mechanical Properties

To avoid mechanical failure of the film and to ensure that film can bear the stress during transportation and storage, the following mechanical properties were measured.

Tensile strength:

Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. It is calculated by the applied load at rupture divided by the cross‐sectional area of the strip . It is given by the equation as followes.

Tensile strength = Load at breakage

Strip thickness × Strip Width

The tensile testing gives an indication of the strength and elasticity of the film, reflected by the parameters - tensile strength, elastic modulus, % strain, and load at yield.

The mechanical properties of the film gives idea about to what extent the film can withstand the force or stress during processing, packaging, transport and handling. The desirable characteristics of film are moderate tensile strength, low elastic modulus, high % strain and high load at yield.

Fig:2 Apparatus set to determine the tensile strength of prepared film

Percent Elongation:

When stress is applied, a strip sample stretches and this is referred to as strain. Strain is basically the deformation of strip divided by original dimension of the sample. Generally elongation of strip increases as the plasticizer content increases.

% Elongation = Increase in length ×100

Original length

Surface pH:

The surface pH of fast dissolving oral thin films was determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may cause irritation to the oral mucosa, it was determined to keep the surface pH as close to neutral as possible. A combined pH electrode was used for this purpose. Oral strip was slightly wet with the help of water. The pH was measured by bringing the electrode in contact with the surface of the film.

Compatibility studies:

The drug-polymer compatibility was confirmed by taking IR spectrum and DSC thermogram of drug, polymer and physical mixture of drug-polymer.

Drug Content and Content Uniformity:

The drug content and content uniformity test was performed to ensure uniform distribution of drug. This is determined by any standard assay method described for the particular API in any of the standard pharmacopoeia. Content uniformity is determined by estimating the API content in individual strip. Limit of content uniformity is 85–115 percent.

In vitro Disintegration and Dissolution Time:

The disintegration time is the time when a film starts to break or disintegrate. Disintegration of orally fast dissolving films requires USP disintegration apparatus. Disintegration time will vary depending on the formulation but typically the disintegration range from 5 to 30 seconds. Although, no official guidance is available for oral fast disintegrating films strips. The dissolution time is the time when the film completely dissolves.

Dissolution test:

Dissolution testing can be performed using the standard basket or paddle apparatus described in any of the pharmacopoeia. The dissolution medium will essentially be selected as per the sink conditions and highest dose of the API. Many times the dissolution test can be difficult due to tendency of the strip to float onto the dissolution medium when the paddle apparatus is employed.

Fourier transform infra red studies:

Infrared absorption spectra are one of the important analytical techniques for chemical identification. The drug and the carrier interaction were studied by FTIR studies. IR spectra of perindoril, Hydroxy Propyl Methyl Cellulose, Poly Ethylene Glycol, Chitosan, was taken on a FTIR (Bruker Alpha IR Spectrophotometer, Chalapathi college, Guntur). The pellets were prepared using KBr press using a mixture of sample and KBr in 1:10 ratio. The spectra were recorded over the wave number range of 4,000 to 600 cm⁻¹. The IR spectra of pure drug and polymers were compared with IR spectra of the powder blend of the various formulations. The absence of appearance or disappearance of characteristic peaks in the spectra confirms that there was no incompatability between the drug and the polymers taken for the study.

Table:1 Formulation design

Formulation code	F1	F2	F3	F4	F5	F6	F7	F8
Perindopril (mg)	4	4	4	4	4	4	4	4
HPMC (mg)	250	250	350	350	450	450	250	250
Chitosan (mg)	125	250	175	350	225	450	-	-
PEG(mg)	-	-	-	-	-	-	125	250
Methanol (ml)	10	10	10	10	10	10	10	10
Propylene glycol (ml)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Sucrose (mg)	10	10	10	10	10	10	10	10

Formulation code	F8	F9	F10	F11	F12	F13	F14	F15
Perindopril (mg)	4	4	4	4	4	4	4	4
HPMC (mg)	250	350	350	450	450	250	350	450
Chitosan (mg)	-	-	-	-	-	-	-	-
PEG(mg)	250	175	350	225	450	-	-	-
Methanol (ml)	10	10	10	10	10	10	10	10
Propylene glycol (ml)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Sucrose (mg)	10	10	10	10	10	10	10	10

Differential scanning calorimetric studies:

Differential scanning calorimetric studies were used to know the compatibility. DSC thermograms of the pure drug and the mixture of drug and excepients were recorded on a thermal analyzer. The samples were heated from 30 to 300°C at a heating rate of 10 °C/min in an inert nitrogen atmosphere. Then the samples give endothermic peaks at particular temperature , if the endothermic peaks of pure drug and mixture f the drug and polymer are nearly appears at the same temperature , then the drug and polymer are said to be compatible.

RESULTS AND DISCUSSION:

Table :2 calibration curve data for perindopril

S.no	Concentration (µg/ml)	Absorbance (210 nm)
1	2	0.025
2	4	0.061
3	6	0.096
4	8	0.134
5	10	0.174

Table : 3 Results of %Drug content:

Formulation	%Drug content	Formulation	% Drug content
F1	88.25	F8	85.02
F2	84.75	F9	72.30
F3	89.00	F10	89.76
F4	84.00	F11	89.05
F5	88.00	F12	90.25
F6	83.50	F13	98.75
F7	96.10	F14	98.50
		F15	98.50

Fourier transform infra red studies:

Fig:3 FTIR results for pure prrindopril, and mixture of drug with various polymers

Fig: 4 Drug release pattren for formulations f1 to f6

Fig: 5 Drug release pattren for formulations f7 to f12

Fig: 6 Drug release pattren for formulations f13 to f15

Results of differential scanning calorimetry:

Fig: 7 Differential scanning calorimetry graph of perindopril ,HPMC, chtosan

Fig: 8 Differential scanning calorimetry graph of perindopril , HPMC and PEG

Fig: 9 Differential scanning calorimetry graph of perindopril and HPMC

Fig: 10 Differential scanning calorimetry graph of perindopril

Table 5 Results of various evaluation parameters:

Formulation	Disintegration Time(sec)	Dissolution time(sec)	Thickness(mm)	Mean weight(mg)
F1	49	159	0.105±0.001	36±3.4
F2	53	169	0.109±0.002	38±1.2
F3	51	162	0.106±0.002	110±7.2
F4	54	160	0.107±0.001	104±8.4
F5	53	163	0.105±0.002	40±1.0
F6	59	167	0.105±0.001	48±2.3
F7	43	145	0.104±0.001	77±1.2
F8	45	147	0.101±0.002	66±1.4
F9	49	148	0.108±0.001	59±1.0
F10	49	152	0.106±0.002	104±2.1
F11	51	156	0.103±0.001	79±0.9
F12	53	160	0.109±0.001	124±4.2
F13	35	120	0.104±0.002	45±1.0
F14	38	127	0.105±0.001	59±1.0
F15	41	135	0.101±0.001	63±2.1

Table : 6 Results of various evaluation parameters:

Formulation	Surface pH of film	%Elongation	Tensile strength(kg/mm²)	% Moisture loss
F1	6.4±0.13	1.125	1.75±0.23	0.029
F2	6.6±0.16	0.930	1.73±0.004	0.021
F3	6.5±0.18	0.935	1.69±0.037	0.017
F4	6.4±0.15	1.10	1.72±0.091	0.023
F5	6.7±0.12	1.125	1.71±0.003	0.032
F6	6.5±0.14	1.150	1.65±0.006	0.028
F7	6.8±0.11	1.150	1.62±0.040	0.040
F8	6.3±0.15	1.175	1.58±0.035	0.016
F9	6.5±0.13	1.187	1.62±0.002	0.017
F10	6.7±0.12	1.196	1.54±0.15	0.019
F11	6.6±0.11	1.225	1.61±0.07	0.021
F12	6.7±0.15	1.175	1.67±0.02	0.028
F13	6.3±0.16	1.225	1.51±0.042	0.020
F14	6.4±0.13	1.203	1.56±0.027	0.016
F15	6.5±0.18	1.150	1.57±0.036	0.017

Table : 7 Results of drug content and content uniformity:

FORMULATION	ABSORBANCE	%AMT DISSOLVED
F1	0.00947	82.81±1.25
F2	0.00904	81.65±1.87
F3	0.00868	79.77±2.34
F4	0.00832	78.00±2.54
F5	0.00868	79.62±1.75
F6	0.0076	75.21±1.89
F7	0.0100	85.07±1.76
F8	0.00697	78.42±2.12
F9	0.00695	81.30±2.65
F10	0.00886	80.27±1.35
F11	0.00868	79.62±2.24
F12	0.00947	82.81±1.76
F13	0.0128	96.75±1.42
F14	0.0121	94.25±1.89
F15	0.01048	87.47±1.54

DISCUSSIONS:

Preparation of standard calibration curve of perindopril:

The λ _max of 210nm was found from UV spectrum of perindopril in distilled water. Standard curve obeyed Beer-Lambert’s law in the concentration range of 2 - 10 μg/ml (R² = 0.999)

Fourier transform infra red studies:

From the FTIR spectra of pure drug and polymers we can say that the polymers used are compatibile with pure drug perindopril.

Drug dissolution studies:

The values of percent amount drug release of perindopril from oral films are given in Table 3 and mean dissolution curves are shown in Fig3-6 The percent amount release for the films containing only HPMC shows more drug release when compared to other films containing mixture of HPMC and PEG and mixture of HPMC and Chitosan along with drug. The increasing order of amount of drug release for various fomulations is in the following order.

F13-F15 > F7-F12 > F1-F6

Differential scanning calorimetry:

The DCS curves of mixture of perindopril , HPMC, chitosan ; mixture of perindopril , HPMC ,PEG ; mixture of perindopril , HPMC and pure perindopril are shown in the fig7-10: respectively. By observing the endothermic peaks we can assure that the ingredients used in the mixture are compatible as all the peaks apper nearly at 130 celsius.

%Drug content:

The values of percent drug content of perindopril from oral films are given in Table 3. The percent drug content for the films containing only HPMC shows more when compared to other films containing mixture of HPMC and PEG and mixture of HPMC and Chitosan along with drug. The increasing order of drug content in various films is in the following order

F13-F15 > F7-F12 > F1-F6

Disintegration time (sec):

The values of disintegration time of oral films are given in Table 5. The disintegration time values for the films containing only HPMC shows less when compared to other films containing mixture of HPMC and PEG and mixture of HPMC and Chitosan along with drug .Hence the films containing only HPMC shows faster disintegration when compared to other films.

Dissolution time (sec):

The values of Dissolution time of oral films are given in Table 5. The Dissolution time values for the films containing only HPMC shows less when compared to other films containing mixture of HPMC and PEG and mixture of HPMC and Chitosan along with drug .Hence the films containing only HPMC dissolves fast, and release drug fast when compared to other films

Drug content and content uniformity:

The values of Drug content and content uniformity of oral films are given in Tables 7. The drug content of F13 –F15 fomulations which are prepared by uing only HPMC are more when compared to other formulations F7-F12 which are made up of mixture of HPMC and PEG ; F1-F6 that are made up of mixture of HPMC and chitosan.

Film thickness:

The values of film thickness of oral films are given in Table 5 . All the formulations have almost uniform thickness in the range of 0.1 ± 0.001 to 0.009.

Mean weight of formulation:

The values of Mean weight of formulation of oral films are given in Table 5 . All the formulations have almost uniform Mean weight in the range of ± 1-5.

%Moisture loss:

The values of %Moisture loss of oral films are given in Table 6 . All the films has values in the decimals range , so there is a minute difference in the % moisture loss of the formulation.

Tensile strength:

The values of %Moisture loss of oral films are given in Table 6. All the films has values kg/mm² , all the films has good tensile strength they range from 1.5 -1.7 kg/mm² .

% Elongation:

The values of %Elongation of the oral films are given in Table 6. All the films has values in the rage of 0.9- 1.2 cm. So by this we can assure that they have good mechanical properties.

Surface pH of film:

The values of %Elongation of the oral films are given in Table 6 . All the films has values in the rage of pH 6.3-6.8, so they all are near to neutral pH , hence these formulations can be used un-doubtly because chance of irritation due to pH is less.

CONCLUSION:

Novel developments in the technology have promoted scientists to develop oral fast dissolving films with improved patient compliance and convenience. This system is oral fast-dissolving film that allows children, elderly and the general population to take their medications discretely wherever and whenever needed, satisfying an unmet need. Oral fast dissolving films are solid unit dosage forms, which dissolve disperse after placement in mouth without chewing and drinking water. It is beneficial for the patients during travelling who do not have access to water. As the oral fast dissolving films utilizes sublingual route, rapid absorption of drug is possible, which finally leads to quick onset of drug action. Novel oral drug disintegrating dosage forms are also known as fast dissolving, rapid dissolving and quick disintegrating film. The Fast Dissolving Oral Films were prepared by Solvent Method. In the preliminary tests, was carried out and no significant drug interaction was observed for peindopril with polymers and excipients. UV scan of perindopril had shown maximum absorption at wavelength 210.0 nm which is specified in pharmacopoeia, textbooks and in literature survey. Preliminary trials of film forming polymer (HPMC,PEG,chitosan.) was studied. All the evaluation tests are performed and results are obtained.

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Received on 13.11.2013 Modified on 16.12.2013

Res. J. Pharm. Dosage Form. and Tech. 6(2):April- June 2014; Page 71-80