Formulation and Evaluation of  Mucoadhesive Fast Melt-Away Wafers Using Selected Polymers

 

Sonte Sushmitha*, Sedimbi Revathi Priyanka, L. Mohan Krishna, M. Srinavasa Murthy

Vignan Institute of Pharmaceutical Sciences, Deshmukhi, Nalgonda-508284, Andhra Pradesh, India

*Corresponding Author E-mail: sonte.sushmitha@gmail.com

In the present study fast dissolving drug delivery system of  Atenolol were successfully developed in the form of mucoadhesive fast melt-away wafers which offers a suitable and practical approach in serving desired objective of faster disintegration and dissolution characteristics with increase in patient compliance by avoiding the first pass metabolism and enhance the bioavailability of the drug and for pediatric, geriatric and un co-operative mentally ill patients.

 

In the present study, mucoadhesive fast melt away wafers of Atenolol were prepared using selected polymers like HPMC E5, HPMC E6, HPMC E15 and PULLULAN by solvent casting method. Films were uniform in weight.  The preformulation studies were carried out and evaluation studies were conducted. Present study reveals that maximum all formulated wafers shown satisfactory film parameters. Formulation (F9) with HPMC E6 400 mg has shown better in vitro dissolution profile compared with other formulations. The in vitro drug release study shown higher drug release (98.83%) in 150 seconds of the wafer with super disintegrate used.

 

Hence, the fast dissolving buccal wafers of Atenolol are expected to provide clinician with a new choice of safe and more bioavailable formulations in the management of hypertension. The study reveals satisfactory results with a further scope of pharmacokinetic and pharmacodynamic evaluation and can be a potential novel drug dosage form for pediatric, geriatric and also for general population.

 

 

 

INTRODUCTION:

Many drugs given orally are poor in bioavailability because of the pH of the stomach, the presence of enzymes, and extensive first-pass metabolism.  Fast- dissolving drug-delivery system came in to existence in the late 1970’s as an alternative to tablets, capsules and syrups for pediatric and geriatric patients who experience difficulty of swallowing traditional oral solid dosage forms. FDDDS are solid dosage forms, which disintegrate or dissolve within 1 min when placed in the mouth without drinking water or chewing.

 

Most of the existing fast dissolving drug delivery systems are in the form of tablets and are designed to dissolve or disintegrate in the patient’s mouth within a few seconds or minutes without the need of water.

 

Research and development in the oral drug delivery segment has led to transition of dosage forms from simple conventional tablets or capsules to modified release tablets or capsules to oral disintegrating tablet (ODT) to flash wafers, mucoadhesive melt away wafers and mucoadhesive sustain release wafers^(1-6)..

 

A wafer or film can be defined as a dosage form that employs a water-dissolving polymer (generally a hydrocolloid, which may be a bioadhesive polymer), which allows the dosage form to quickly hydrate, adhere and dissolve when placed on the tongue or in oral cavity  instantly wet by saliva. The wafer quickly hydrates, adheres, then rapidly disintegrates and dissolves to release the medication for mucosal and intragastric absorption when placed on the tongue or in the oral cavity to provide rapid local or systemic drug delivery. Hence patient compliance is more in patients with difficulty in swallowing and chewing. And more than all this bioavailability of drug is significantly greater than the conventional tablet dosage form bypassing first pass metabolism.These wafers are flexible strips similar in size, shape and thickness to a postage stamp (2x3 cm) and can be packaged in multidose containers or individually pouch⁶.

 

The thickness of a typical wafer ranges from 1-10mm and its surface area can be 1-20cm². An ideal wafer should be thin, flexible, elastic and soft, yet adequately strong to withstand breakage due to stress from mouth movements, printable, low-moisture, non tacky film suitable for dosing and labeling. It must also posses good bioadhesive strength in order to be retained in the mouth for the desired duration of action^(7,8).

 

Ideal characteristics of drug choosing for wafes include pleasant taste, smaller or moderate molecular weight, stability and solubility in water as well as saliva. It should be partially unionized at the pH of oral cavity and  has to penetrate the oral mucosa. Here Atenolol was selected for the preparation of wafer by solvent casting method. ^(9-14) .

 

MATERIALS AND METHODS:

Materials:

Atenolol was received as gift sample from IPCA Laboratories Limited, Aurangabad. HPMC E15, HPMCE5, HPMC E6 ,pullulan, PEG-400, glycerine and  crosspovidone were purchased from Essel fine chemicals, Mumbai. Aspertame, Ascorbic acid, Menthol were purchased from S.D. Fine Chemicals Ltd, Chennai.

 

Methods:

FTIR Studies:

The drug and polymer interaction studies were carried out by using FT-IR studies and resulted spectra is shown in fig.01.

 

Dose of Atenolol:

The amount of Atenolol required i.e 25mg per 1sq.cm of wafer was calculated.

 

Preparation of oral fast dissolving film:

The fast dissolving wafers of Atenolol were prepared by solvent casting technique. The fast dissolving films were prepared using different polymers like HPMC E5, HPMC E6, HPMC E15 and Pullulan (Tab.01; Formulation chart). Polyethylene glycol-400(PEG400) was used as plasticizer. The calculated amount of polymer was dispersed in the solvent with continuous stirring using magnetic stirrer and the homogenous solution is formed. Then add 3 drops of plasticizer. Then the sweetener and flavor were added to drug mixed polymeric solution. Then the solution was kept in sonicator for degassing. Then the bubble free solution was casted on to petriplate and was kept in hot air oven. Dried film is then cut into the desired shape and size (1cm x 1cm) for the intended application. By carrying out the trial and error method different concentrations (2%, 3% and 4%) of film forming polymers were used for optimizing the formulation.

 

Thickness:

As the thickness of wafer is directly concern with drug content uniformity. Thickness test was calibrated digital Verniar Calipers. The thickness of the film sample should be measured at five locations (center and four corners), and the mean thickness is calculated. Typical thickness for wafers was given in the table 03.

 

Folding endurance:

It was determined by repeated folding of the strip at the same place till the strip breaks. The number of times the film is folded without breaking is computed as the folding endurance value. Typical folding endurance for film is give in the table 0.3.

 

Swelling index: 

The studies of swelling index of the film were conducted in simulated salivary fluid (table 02). The wafer sample is weighed and placed in a pre-weighed stainless steel wire sieve  of approximately 800-µm mesh .The mesh containing the wafer was submerged into 50ml of simulated salivary medium contained in a container. Increase in weight of the film is determined at each interval until a constant weight is observed. The degree of swelling is calculated using the formula:

Where, SI = swelling index,

Wt = weight of the wafer at time “t”, and

wo = weight of the film at t = 0

 

 

 

Table 01-Formulation chart

SAMPLE	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Drug	433.5	433.5	433.5	433.5	433.5	433.5	433.5	433.5	433.5	433.5	433.5	433.5
HPMC E15(mg)	200	300	400	-	-	-	-	-	-	-	-	-
HPMC E5(mg)	-	-	-	200	300	400	-	-	-	-	-	-
HPMC E6(mg)	-	-	-	-	-	-	200	300	400	-	-	-
PULLULAN(mg)	-	-	-	-	-	-	-	-	-	200	300	400
METHANOL(ml)	1	1	1	1	1	1	1	1	1	1	1	1
ASPERTAME(mg)	50	50	50	50	50	50	50	50	50	50	50	50
ASCORBIC ACID(mg)	25	25	25	25	25	25	25	25	25	25	25	25
PEG-400 (drops)	2	2	2	2	2	2	2	2	2	2	2	2
GLYCERINE(drops)	1	1	1	1	1	1	1	1	1	1	1	1
Cross Povidone(ml)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Water(ml)	10	10	10	10	10	10	10	10	10	10	10	10

Weight uniformity of films:

Wafer (size of 1 cm²) was taken from different areas. The weight variation of each wafer is calculated by weighing on the electronic weighing balance. The result is given        table 03.

 

Drug Content uniformity:

The wafers were tested for drug content uniformity by UV Spectrophotometric method. The results are given table 02.

 

 Invitro Disintegration time:

The invitro disintegration time of fast dissolving wafers was determined visually in a glass dish of 8 ml 6.8 pH phosphate buffer with swirling action. Typical disintegration time for wafer is 5-30 sec. The results are given table 02.

 

Moisture uptake:

The moisture uptake of the wafers was determined by exposing them to a environment of 400C with 75% relative humidity for 1 week. The uptake of moisture by the films was calculated with percent increase in weight. The results are given table 03.

 

Invitro Dissolution Study :

Invitro dissolution of Atenolol wafers were studied in paddle type dissolution test apparatus. 900ml of 6.8 phosphate buffer solution was used as dissolution medium at 50rpm. Drug release was measured at 224nm. The results are given table 04 and Fig 0.2.

 

Stability study:

Stability studies for selected formulations were carried out by storing in amber colored bottle tightly plugged with cotton and capped at 40±0.50C and 75.0± 5% RH for 3 month. The formulations were evaluated for physical appearance, drug content and in vitro dispersion time at one month interval time. For stability testing the oral wafers were stored under controlled conditions of 25 °C / 60 % RH as well as 40 °C/ 75 % RH over a period of 12 months according to the ICH guideline. The results are given table 05.

 

In the IR spectrum of the optimized formulae i.e., drug Atenolol and polymer HPMC E6 indicates the presence of (OH) Hydroxyl group’s absorption at 3401cm-1. And at 3370 cm-1 Amide group is present which indicates the presence of these groups in the molecule. And at 2901 cm-1 C-CH₃ Stretching was found which indicates aliphatic alkanes. And in this at 2885 cm-1 CH₂ groups are present .Hence from this we can found that there are no interactions between drug and polymers.

 

 

RESULTS AND DISCUSSION:

 

Fig.01-FTIR of pure drug + Polymer HPMC E 6

 

 

 

Table 02-Content uniformity, In-vitro Disintegration, Swelling Index

Formulation  Code	Drug Content Uniformity (%) ±SD, n=3	In vitro Disintegration (sec) ±SD, n=3	swelling index (%) ± SD, n =3
F1	93.91 ± 0.047	19 ± 3.606	64.65 ± 2.263
F2	91.90 ± 0.056	12 ± 1.000	60.24 ± 2.234
F3	94.94 ± 0.035	18 ± 2.517	58.33 ± 3.608
F4	94.94 ± 0.035	12 ± 2.887	65.27 ± 2.402
F5	92.33 ± 0.027	11 ± 1.000	62.22 ± 3.845
F6	91.27 ± 0.043	15 ± 2.517	56.60 ± 5.920
F7	95.63 ± 0.032	08 ± 1.051	54.66 ± 3.395
F8	96.85 ± 0.041	09 ± 2.887	69.08 ± 3.608
F9	98.68 ± 0.034	06 ± 2.646	71.16 ± 3.608
F10	91.27 ± 0.043	28 ± 2.517	63.80 ± 3.920
F11	89.55 ± 0.025	25 ± 3.606	65.79 ± 4.440
F12	88.33 ± 0.027	22 ±1.0	68.16 ± 3.608

 

Table 03-Weight variation, Moisture uptake, thickness and Folding Endurance

Formulation Code	Weight (mg) ±SD, n=3 ­	Moisture uptake	Thickness (mm) ±SD, n=3	Folding  Endurance ± SD, n=3
F1	48.00 ± 1.000	Nil	1.1 ±0.115	154 ±2.554
F2	47.66 ± 1.528	Nil	1.1 ±0.057	185 ±3.325
F3	60.21 ± 1.000	Nil	0.9 ±0.057	175 ±3.651
F4	47.32 ± 1.432	Nil	0.1 ±0.010	142 ±2.124
F5	51.10 ± 0.522	Nil	0.7 ±0.152	146 ±2.326
F6	59.10 ± 0.574	Nil	0.9 ±0.200	142±3.964
F7	56.25 ± 0.362	Nil	0.8 ±0.173	112  ±2.351
F8	57.45 ± 0.220	Nil	0.8 ±0.100	122 ±3.239
F9	59.29 ± 1.210	Nil	0.8 ±0.102	123 ±3.164
F10	49.27 ± 0.572	Nil	0.8 ±0.057	82 ±2.875
F11	59.14 ± 0.528	Nil	0.9 ±0.057	85 ±2.421
F12	60.00 ± 1.00	Nil	0.9 ±0.100	76 ±2.021

Among all the formulations, Formulation F7 to F9 showed minimum folding endurance time which indicates that these fast dissolving films are excellent in flexibility as compared to other formulations.

 

Table 04-In vitro drug release profile of Atenolol from F1 to F12

 

Table 05-Stability data of fast dissolving oral films of Atenolol

parameters	before storage	after 3 months
physical  appearance	Result	No change
weight uniformity(mg)	59.29 ± 1.210	59.01
disintegration time(sec)	06 ± 2.646	08 ± 2.646
folding endurance	123 ±3.164	121 ±3.164
content  uniformity(%)	98.68 ± 0.034	98.38 ± 0.034
Swelling index(%)	71.16 ± 3.608	70.16 ± 2.408
% drug release	98.83	98.23
Thickness(mm)	0.8 ±0.102	0.7 ±0.101
Moisture uptake	Nil	Nil

 

Fig.02-In-vitro drug release profile of wafers(F1- F12) of Atenolol.

 

Fig 0.3-In-vitro drug release profile of wafer(F9) of Atenolol.

 

CONCLUSION:

The present study was undertaken with an intention to develop buccal fast melt-away wafers of Atenolol. Atenolol is soluble in water but its bioavailability is limited. Hence this fast melt-away wafer was useful for the improving of the bioavailability of the drug. These wafers were prepared using HPMC (E5, E6, and E15) and Pullulan polymers by solvent casting method.

 

Present study reveals that maximum all formulated films showed satisfactory film parameters. Formulation (F9) with HPMC E6 400 mg has shown better in vitro dissolution profile (98.83%) in 150 seconds(Fig 0.3), compared with other formulations. Hence, the fast melt-away wafers of Atenolol are expected to provide clinician with a new choice of safe and more bioavailable formulations in the management of hypertension.

 

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Received on 17.10.2013       Modified on 04.11.2013

Accepted on 15.12.2013      © RJPT All right reserved